Opsin evolution: Cytoplasmic face: Difference between revisions

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'''See also:''' [[Opsin_evolution|Curated Sequences]] | [[Opsin_evolution:_ancestral_introns|Ancestral Introns]] | [[Opsin_evolution:_informative_indels|Informative Indels]] | [[Opsin_evolution:_ancestral_sequences|Ancestral Sequences]] | [[Opsin_evolution:_alignment|Alignment]] | [[Opsin_evolution:_update_blog|Update Blog]]
=== Comparative genomics of the cytoplasmic face of GPCR proteins ===  
=== Comparative genomics of the cytoplasmic face of GPCR proteins ===  


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  MEL2_anoCa DRYCVITKPLQSIKRTSKKR TCIIIVFVW 20 T P Gq
  MEL2_anoCa DRYCVITKPLQSIKRTSKKR TCIIIVFVW 20 T P Gq


While it might seem straightforward to thread any opsin onto its best fit among the five newly available crystallographic structures, that does not work for distantly related paralogs beyond the universal 7-transmembrane feature because loop regions can be of quite different length and so lack discernable alignability, having diverged greatly in amino acid sequence (even though they are all ultimately homologous).  
While it might seem straightforward to thread any opsin onto its best fit among the five newly available crystallographic structures, that does not work for distantly related paralogs beyond the universal 7-transmembrane feature because loop regions can be of quite different length and so lack discernible alignability, having diverged greatly in amino acid sequence (even though they are all ultimately homologous).  


While these structures entail various compromises (such as replacemente of C3 by lysozylme and deletion of carboxy tail to enable stable crystallization), they are hugely important to annotation transfer of sequence/function relationships via comparative genomics. Yet most of the 18 vertebrate opsin orthology classes have only remote models to date and even these can be indeterminate for mid-loop C2 residues (indicative of flexible conformation).
While these structures entail various compromises (such as replacements of C3 by lysozyme and deletion of carboxy tail to enable stable crystallization), they are hugely important to annotation transfer of sequence/function relationships via comparative genomics. Yet most of the 18 vertebrate opsin orthology classes have only remote models to date and even these can be indeterminate for mid-loop C2 residues (indicative of flexible conformation).


  Gene          PDB            Protein                    PubMed      Best human opsin  Next Best        Signaling
  Gene          PDB            Protein                    PubMed      Best human opsin  Next Best        Signaling
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The squid melanopsin structure, submitted online to SwissModel, could otherwise predict the structure of the cytoplasmic loops of all opsins of melanopsin class, of which 48 vertebrate sequences, 9 lophotrochozoan, 43 arthropod, and 1 cnidarian sequences are available [[Opsin evolution|here]].  
The squid melanopsin structure, submitted online to SwissModel, could otherwise predict the structure of the cytoplasmic loops of all opsins of melanopsin class, of which 48 vertebrate sequences, 9 lophotrochozoan, 43 arthropod, and 1 cnidarian sequences are available [[Opsin evolution|here]].  


The Gq signalling partner will be used throughout these melanopsins, yet what features the Galpha protein specifically recognizes in the cytoplasmic face remain obscure. It cannot really be the terminal helical extension per se because squid Gq protein will prove structualy homologous to its 16 paralogs (in vertebrates) of different signaling types, meaning some universally conserved feature must be utilized instead.
The Gq signalling partner will be used throughout these melanopsins, yet what features the Galpha protein specifically recognizes in the cytoplasmic face remain obscure. It cannot really be the terminal helical extension per se because squid Gq protein will prove structuraly homologous to its 16 paralogs (in vertebrates) of different signaling types, meaning some universally conserved feature must be utilized instead.
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=== The first cytoplasmic loop ===
=== The first cytoplasmic loop ===


This can be defined from bovine RHO1 and squid melanopsin structures or by bioinformatic calculation of transmembrane helices. Note the three online tools for that seldom agree with each other or xray structures (which have artefacts of their own). Here best representatives for each opsin class were found by blastp against SwissProt and the cytoplasmic loop taken from SwissProt annotation. It emerges that that a highly conserved glutamate in transmembrane helix 2 must be a fixed number of residues in (namely 10) to conserve its helical wheel position with respect to the overall membrane structure and residues with which it interacts.  
This can be defined from bovine RHO1 and squid melanopsin structures or by bioinformatic calculation of transmembrane helices. Note the three online tools for that seldom agree with each other or xray structures (which have interpretive artifacts of their own). Here best representatives for each opsin class were found by blastp against SwissProt and the cytoplasmic loop taken from SwissProt annotation. It emerges that that a highly GPCR-conserved glutamate in transmembrane helix 2 must be a fixed number of residues in (namely 10) to conserve its helical wheel position with respect to the overall membrane structure and residues with which it interacts. This aspartate is known to hydrogen bond to Asn55 on TM1 (GFPIN) and main chain Ala299 in TMH7 (AKTSA), thus organizing the relationship of TM1,2,7 in the vicinity of the Schiff base.


Consequently, cytoplasmic loop 1 must end at the PLN motif of RHO1 and hence all other opsins. The beginning of the cytoplasmic loop can be defined by similar considerations. It emerges from a mega-alignment that every opsin is indel-free in this region. Thus all CL1 must be of the same length (12 amino acids). Some sequence conservation, notably the proline at position 9, is universal. This proline may break the continuation of membrane alpha helix from the cytoplasmic domain into the cytoplasm. Internal basic residues are also found consistently.
Consequently, cytoplasmic loop 1 must end at the PLN motif of RHO1 and hence all other opsins. The beginning of the cytoplasmic loop can be defined by similar considerations. It emerges from a mega-alignment that every opsin is indel-free in this region. Thus all CL1 must be of the same length (12 amino acids). Some sequence conservation, notably the proline at position 9, is universal. This proline may break the continuation of membrane alpha helix from the cytoplasmic domain into the cytoplasm. Internal basic residues are also found consistently.
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On the basis of length (19 to rhodopsin, 20 to melanopsin), all the opsins except encephalopsin and RGR (both 16 residues) and TMT (18 residues subsequent to a  deletion in amniote stem) have a structural model. This model is further constrained by predictable helical extensions of transmembrane helices into the cytoplasm, leaving only the mid-loop region to be predicted. It's not clear whether observed residue conservation -- both within and across orthology classes -- derives from structural importance or instead to Galpha binding specificity requirements.
On the basis of length (19 to rhodopsin, 20 to melanopsin), all the opsins except encephalopsin and RGR (both 16 residues) and TMT (18 residues subsequent to a  deletion in amniote stem) have a structural model. This model is further constrained by predictable helical extensions of transmembrane helices into the cytoplasm, leaving only the mid-loop region to be predicted. It's not clear whether observed residue conservation -- both within and across orthology classes -- derives from structural importance or instead to Galpha binding specificity requirements.


The adenosine and adrenergic receptor structures -- however useful they might be for annotation transfer to the other 350 non-oderant human GPCR -- ultimately will not prove helpful in modeling the second cytoplasmic loop of opsins (squid melanopsin does that better already). Note C2 in these three structures is consistently stablized by a mid-loop hydrogen bond to the DRY residues. This constraint is not observed in squid melanopsins or other metazoan opsin classes; indeed it is not feasible because no hydrogen bond-capable residue consistently occurs there (in the comparative genomics sense of conserved residue). Ancestrally, this mid-loop bridge might be a derived feature fairly early in the stem of non-opsin GPCR.
The adenosine and adrenergic receptor structures -- however useful they might be for annotation transfer to the other 350 non-oderant human GPCR -- ultimately will not prove helpful in modeling the second cytoplasmic loop of opsins (squid melanopsin does that better already). Note C2 in these three structures is consistently stabilized by a mid-loop hydrogen bond to the DRY residues. This constraint is not observed in squid melanopsins or other metazoan opsin classes; indeed it is not feasible because no hydrogen bond-capable residue consistently occurs there (in the comparative genomics sense of conserved residue). Ancestrally, this mid-loop bridge might be a derived feature fairly early in the stem of non-opsin GPCR.


[[Image:OpsinCyto2Five.jpg]]
[[Image:OpsinCyto2Five.jpg]]
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(to be continued)
(to be continued)


== The third cytoplasmic loop in melanopsins ==
== The third cytoplasmic loop in 83 melanopsins ==


This loop may be an important contributer to the Gq specificity. The structure has been determined for [http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=2Z73 squid melanopsin], denoted MEL_todPac below. It is a typical 'HEK' extended-helix CL3 found in vast majority of protostome melanopsins. However deuterostome melanopsins never have this feature, yet also appear to signal through Gq. Melanopsin introns within this motif are  considered [[Opsin_evolution:_ancestral_introns#Ancestral_melanopsin_intronation|elsewhere]].
The orphan Drosophila opsin RH7, which has not yet been associated with an anatomical structure, also lacks the HEK feature and is considerably shorter. However, as the lower sequences in the alignment below show, length variability is by no means unprecedented in this melanopsin loop. Indeed, the one cnidarian opsin available also lacks the HEK motif and also the length of those motifs.
The HEK motif is not specific to wavelength or ommatidia position as the full gamut of drosophila opsins RH1-RH6 have the feature. The motif specifically co-occurs with conserved A.K and more distal A..A  whereas a more distal E....K motif are almost universal to all melanopsins -- indeed the E is universal to all opsins (except RGR and peropsin) but not other GPCR. Curiously RH7 has phenylalanine in place of K here. Alanine is inert in terms of side chain potential for interactions, so its conservation is a bit puzzling.
[[Image:HEKopsin.jpg]]
gene        transmembrane helix 5        cytoplasmic loop CL3            transmem helix 5
RH1_droMel  YYIPLFLICYSYWFIIAAVSA HEKAMREQAKKMN--VKSLRSSEDAE---KSA-EGKLAK VALVTITLWFMAWTPY
RH2_droMel  YYTPLFLICYSYWFIIAAVAA HEKAMREQAKKMN--VKSLRSSEDCD---KSA-EGKLAK VALTTISLWFMAWTPY
LWS1_apiMe  YYTPLFTIIYSYYFIVSAVAA HEKAMKEQAKKMN--VTSLRSGDNQN---TSA-EAKLAK VALTTISLWFMAWTPY
LWS2_apiMe  YFVPLFLIIYSYWFIIQAVAA HEKNMREQAKKMN--VASLRSSENQN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_bomTer  YFFPLFLIIWSYWFIiQAVAA HEKNMREQAKKMN--VASLRSSENQN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_catBom  YFLPLFLIIYSYFFIIQAVAA HEKNMREQAKKMN--VASLRSAENQS---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_papXut  YYTPLLLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSEAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_manSex  YFLPLLLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSEAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_vanCar  YFSPLFLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSDAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_helSar  YYAPLFLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSDAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_pieRap  YFLPLFLIVYSYWFIVQAVAA HERAMREQAKKMN--VASLRSSEQAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_triCas  YFVPLFTIIYSYWFIVQAVAA HEKSMREQAKKMN--VASLRSSEAAQ---TSA-ECKLAK IALMTITLWFFAWTPY
LWS_rhoPro  YFLPLFTIIYSYFFILQAVSA HEKQMREQAKKMN--VASLRSAEAAN---TSA-EAKLAK VALMTISLWFMAWTPY
LWS_schGre  YLLPLGTIIYSYFFILQAVSA HEKQMREQRKKMN--VASLRSAEASQ---TSA-ECKLAK VALMTISLWFFGWTPY
LWS_meoOer  YIGPLALIIYCYFHIVSAVAT HEKQMRDQAKKMG--VKSLRTEEAKK---TSA-ECRLAK VALTTVSLWFMAWTPY
LWS_neoOer  YIGPLALIIYCYFHIVSAVAT HEKQMRDQAKKMG--VKSLRTEEAKK---TSA-GCRLAK VALTTVSLWFMAWTPY
LWS_camLud  YFLPLAITIYCYVFIIKAVAA HEKGMRDQAKKMG--IKSLRNEEAQK---TSA-ECRLAK IAMTTVALWFIAWTPY
LWS_proMil  YFLPLTITIYCYVFIIKAVAA HEKGMRDQAKKMG--IKSLRNEEAQK---TSA-ECRLAK IAMTTVALWFIAWTPY
LWS_eupSub  YLFPFFIIVYCYTYIVSAVFA HEKGMRDQAKKMG--VKSLRNEEAQK---TSA-ECRLAK VALVTVSLWFIAWTPY
LWS_homGam  YFLPLVIIVYCYTYIVAAVSA HERQMREQAKKMG--VKSLRSEESKK---TSN-ECRLAK VALTTVSLWFIAWTPY
LWS_arcGre  YYTPLLYIIYAYTFIVQAVSA HEKGMREQAKKMG--VKSLRNEEAQK---TSA-ECRLAK VALMTVSLWFMAWTPY
LWS_holCos  YLFPLAYIIYSYTFIVKAVAA HEKGMREQAKKMG--VKSLRSEEAQK---TSA-ECRLCK VALMTVTLWFMAWTPY
LWS_neoAme  YIFPLFLNIYLYTFIIKAVAN HEKQMREQAKKMG--VKSLRSEESQK---TSA-ECRLAK VALMTVSLWFMAWTPY
LWS_mysDil  YFIPLGITIYCYSYIVHAVAN HEKSMKEQAKKMG--VKSFRNEETQR---TSA-EFRLAK IALMTVSLWFIAWTPY
LWS_pedHum  YFLPLFIIIYSYIFIIQAVID HENNMRMQAKKME--VASLRSQDDKK---KSV-EIKLAK IALMTIALWFFAWTPY
RH6_droMel  YLTPLLTIIFSYWHIMKAVAA HEKAMREQAKKMN--VASLRNSEADK---SKAIEIKLAK VALTTISLWFFAWTPY
MWS_limPol  YALPLMVIIYCYIFIVKAVCD HERHLREQAKKMN--VASLRSNVDTQ---KASAEMRIAK VALVNVLLWVVSWTPY
BCR_limPol  YALPLMVIIYCYIFIVKAVCD HERHLREQAKKMN--VASLRSNVDTQ---KASAEMRIAK VALVNVLLWVVSWTPY
BCR_dapPul  YCVPLIIIIFCYYHIVRAIVH HEDALRDQAKKMN--VSSLRSNADQK---SQSAEIRVAK IAMMNITLWVAAWTPY
LWS_limPol  YFLPLITMIYCYFFIVHAVAE HEKQLREQAKKMN--VASLRANADQQ---KQSAECRLAK VAMMTVGLWFMAWTPY
LWS2_plePa  YFIPLFTLIYNYTFIVRAVSI HEDNLREQAKKMN--VTSLRANADQQ---KQSAECRLAK IALMTVGLWFIAWTPY
LWS2_hasAd  YFTPLFTLIYNYTFIVRSVSI HENNLREQAKKMN--VSSLRANADQQ---KQSAECRLAK IALMTVGLWFIAWTPY
LWS_ixoSca  YWTPLFINIYCYSKIVRAVAQ HEKQLRLQARKMN--VASLRANAEQT---KTSAEARLAK IALMTVGLWFMAWTPY
LWS1_plePa  YFVPLFIIIYCYTYIVMQVAA HEKSLREQAKKMN--IKSLRSNEDNK---KASAEFRLAK VALMTICLWFMAWTPY
LWS1_hasAd  YFVPLFIIIYCYAFIVMQVAA HEKSLREQAKKMN--IKSLRSNEDNK---KASAEFRLAK VAFMTICCWFMAWTPY
MWS_hemSan  FFLPASVIVFSYVFIVKAIFA HEAAMRAQAKKMN--VTNLRSNEAET---QRA-EIRIAK TALVNVSLWFICWTPY
RH3_droMel  FVCPTTMITYYYSQIVGHVFS HEKALRDQAKKMN--VESLRSNVDKN---KETAEIRIAK AAITICFLFFCSWTPY
RH4_droMel  FVCPTLMILYYYSQIVGHVFS HEKALREQAKKMN--VESLRSNVDKS---KETAEIRIAK AAITICFLFFVSWTPY
UVV_camAbd  YCVPMLLIIYYYSQIVGHVVS HEKALREQAKKMN--VESLRSNVNTN---AQSAEIRIAK AAITICFLFVLSWTPY
UVV_catBom  YCIPMSLIIYYYSQIVSHVVN HEKALREQAKKMN--VESLRSNTNTN---AQSAEIRIAK AAITICFLFVLSWTPY
UVV_apiMel  YCIPMILIIYYYSQIVSHVVN HEKALREQAKKMN--VDSLRSNANTS---SQSAEIRIAK AAITICFLYVLSWTPY
UVV_rhoPro  YVIPMSLIIYFYSQIVSHVII HEHNLREQAKKMN--VESLRSNANMH---TQSAEIRIAK AAITICFLFVASWTPY
UVV_manSex  YVFPMSLIIYFYSGIVKQVFA HEAALREQAKKMN--VESLRANQGGS---SESAEIRIAK AALTVCFLFVASWTPY
UVV_papXut  YIFPMIAILYFYSGIVKQVFA HEAALREQAKKMN--VDSLRSNQNAA---AESAEIRIAK AALTVCFLYVASWTPY
UVV_pedHum  YVLPLSLIIYFYTKIVLHVIN HEKSLKAQAKKMN--VESLRSDGNKN----YAVEIRITK VAIAMCFLFVISWTPY
UVV_dapPul  YVIPLAMLIFYYSKIVRSVGD HEKTLRDQAKKMN--VTSLRSNRDQN---EKSAEVRIAK VAIALATLFVFAWTPY
BLU_manSex  YCIPMALICYFYSQLFGAVRL HERMLQEQAKKMN--VKSLASNKEDN---SRSVEIRIAK VAFTIFFLFICAWTPY
BLU_apiMel  YVIPLIFIILFYSRLLSSIRN HEKMLREQAKKMN--VKSLVSN-QDK---ERSAEVRIAK VAFTIFFLFLLAWTPY
RH5_droMel  YVIPMTMILVSYYKLFTHVRV HEKMLAEQAKKMN--VKSLSANANAD---NMSVELRIAK AALIIYMLFILAWTPY
UVV_plePay  WFIPVAAIVFFYVQIFLAVKD HEEKIKEQARKMN--VDSIRSNEAVK---NSSAEVRIAK TAMCVFLMFLSSWAPY
UVV_hasAda  WFIPVAAIIFFYAQIFLAVKD HEEKIKEQARKMN--VDSFRSNEALK---NSSAEVRIAK TAMCVVLLFLTSWVPY
MEL_plaDum  FIFPVAIIFFCYLGIVRAIFA HHAEMMATAKRMG--A-N--TGKADA---DKKSEIQIAK VAAMTIGTFMLSWTPY
MEL_lotGig  FVVPLGVIIFCYVFIIKSVMN HEKEMAKMADKLD--AKD--VRSTKE---KAKAEIKIAK VSMTIILLYLMSWTPY
MEL_sepOff  FCFPILIIFFCYFNIVMAVSN HEKEMAAMAKRLN--AKE--LRKAQA---GASAEMKLAK ISIVIVTQFLLSWSPY
<span style="color: #FF0000;">MEL_todPac</span>  FFGPILIIFFCYFNIVMSVSN <span style="color: #FF0000;">HEKEMAAMAKRLN--AKE--LRKAQA---GANAEMRLAK</span> ISIVIVSQFLLSWSPY
MEL_entDof  FMLPIIIIAFCYFNIVMSVSN HEKEMAAMAKRLN--AKE--LRKAQA---GASAEMKLAK ISMVIITQFMLSWSPY
MEL_schMed  FIIPVGIIIFCYYQIVKAVRV HELEMLKMAQKMN--ASHPTSMKTGA----KKADVQAAK ISVIIVFLYMLSWTPY
MEL_patYes  FLIPLIIIGVCYVLIIRGVRR HDQKMLTITRS----MKTEDARANNK---RARSELRISK IAMTVTCLFIISWSPY
MEL_schMan  FLCPVFIIIFSYYQIVKTVRL NELELMKMAQSLD--LQNPSAMKTGG---DKKADIEAAK TSIILVLLYLMSWSPY
MEL_homSap  FFLPLLIIIYCYIFIFRAIRE TGRALQTFGAC----KGNGESLWQRQ---RLQSECKMAK IMLLVILLFVLSWAPY
MEL_rheMac  FFLPLLIIIYCYIFIFRAIRE TGRALQTFGAC----KGSGESLWQRQ---RLQSECKMAK IMLLVILLFVLSWAPY
MEL_bosTau  FFLPLLIIIYCYIFIFKAIRE TGQALQTFGTC----EGGSECPRQRQ---RLQNEWKMAK IELLVILLFVLSWAPY
MEL_proCap  FFLPLLVIIYCYVFIFKAIRE TGRALQTFGAC----EGASETPRQWQ---RLQSEWKMAK IALLAILLYVLSWAPY
MEL_galGal  FFIPLIAIIYSYVFIFEAIKK ANKSVQTFGCK----HGNRELQKQYH---RMKNEWKLAK IALIVILLYVISWSPY
MEL_monDom  FFIPLIVIIYCYIFIFRAIQD TNKAVHSIGSG-----ESTASPRHCQ---RMKNEWKMAK IALVVILLYVLSWAPY
MEL_xenTro  FFIPLFIIIYCYIFIFKAIKN TNRAVQKIGTD-----NNKESHKQYQ---KMKNEWKMAK IALIVILLYVVSWSPY
MEL_danRer  FFIPLIVIIYCYFFIFRSIRT TNEAVGKINGD-----NKRDSMKRFQ---RLKNEWKMAK IALIVILMYVISWSPY
MEL_gasAcu  FFLPLFIIIYCYFFIFRAIRV TNRAVGKMNGSIHSHGSGRDSTKNFH---RLQNEWKMAK IALIVILLYVVSWSPY
MEL_braFlo  YFIPMGVIIYCYYNIFATVKS GDKQFGKAVKEMAHE-DVKNKAQQER---QRKNEIKTAK IAFIVITLFLSAWTPY
MEL_strPur  FVVPVTIIIVCFTRIAITVRA HRHELNKMRTKLTEDKDKKHKSSIRR-ANKAKTEFQIAK VGFQVTIFYVLSWMPY
MEL_dapPul  FFLPVSVLTFCYAAIFRFILR SSKEITRLIMTSDGTTSFSKSTVSFR-KRRRQTDVRTAL IILSLAILCFTAWTPY
BLU_dapPul  WVCPLTIITFCYAAIVRAVYR VRQNVTRV---PSQPIDNKHLHQCIN---QPNVEIAIPK IVAGLVLSWIIAWTPY
MEL2_schMa  FLCPLFLSLFCYARIILIVRS RGKDFIEM---AASSKGTNQKEKSAN-VSSSKSDTFVSK SSAILLGVYLICWTPY
MEL3_schMa  FMFPVLLCIYCYVNLLKIVRN NERVVLIS---LSNDGASKQRESVRN---RKRLDIEATK SVILSLLFYLMSWTPY
MEL_aplCal  FVLPFALMVFSYFRIWVAVRK VKSGNVFCAIRHNYNLALGSTLFVKQHRYRLHCEQKTVK IIMFLLIAFTVSWSPY
MEL2_lotGi  FVLPLCFILFAYSRILHLISS HSR--EMKSYRSAVIISKGKASIPKRFR----SERKTAI TLLITVVVFCLSWVPY
MEL_helRob  FGMPVSVIILSYIGIIRSIAK NRKEFSSLTAENSS---------------RARQEIKIAK VFAVCMTAFILCWVPY
MEL_acrMil  YFVPLAIIVYCYVFMIRSVRF MTKNAQKIW--------GVRSAAALE---TVQATWKMAK IGLIMVVGFFVAWTPY
RH7_droMel  YCIPLTSIVYSYFYILKVVFT ASRIQS-----NKD---------------KAKTEQKLAF IVAAIIGLWFLAWSPY
RH7_droYak  YCIPLTSIVYSYFYILKVVFT ASRIQS-----NKD---------------KAKTEQKLAF IVAAIIGLWFLAWSPY
RH7_droPse  YCVPLTTIVYSYFYILKVVFT ASRIQS-----NKD---------------KAKTEQKLAF IVAAIIGLWFLAWSPY
RH7_droGri  YCIPLTCIVYSYFYILKVVFT ANRIQS-----SKD---------------KAKTEQKLTF IVAAIIGLWFIAWSPY
UVV_ixoSca  WCVPLVFVTTCYSGILVTVIR SRKALA-----QES---------------R-RSELRVAK VSLALVLLWTVAWTPY
RH1_droMel  YYIPLFLICYSYWFIIAAVSA HEKAMREQAKKMN--VKSLRSSEDAE---KSA-EGKLAK VALVTITLWFMAWTPY
RH2_droMel  YYTPLFLICYSYWFIIAAVAA HEKAMREQAKKMN--VKSLRSSEDCD---KSA-EGKLAK VALTTISLWFMAWTPY
LWS1_apiMe  YYTPLFTIIYSYYFIVSAVAA HEKAMKEQAKKMN--VTSLRSGDNQN---TSA-EAKLAK VALTTISLWFMAWTPY
LWS2_apiMe  YFVPLFLIIYSYWFIIQAVAA HEKNMREQAKKMN--VASLRSSENQN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_bomTer  YFFPLFLIIWSYWFIXQAVAA HEKNMREQAKKMN--VASLRSSENQN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_catBom  YFLPLFLIIYSYFFIIQAVAA HEKNMREQAKKMN--VASLRSAENQS---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_papXut  YYTPLLLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSEAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_manSex  YFLPLLLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSEAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_vanCar  YFSPLFLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSDAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_helSar  YYAPLFLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSDAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_pieRap  YFLPLFLIVYSYWFIVQAVAA HERAMREQAKKMN--VASLRSSEQAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_triCas  YFVPLFTIIYSYWFIVQAVAA HEKSMREQAKKMN--VASLRSSEAAQ---TSA-ECKLAK IALMTITLWFFAWTPY
LWS_rhoPro  YFLPLFTIIYSYFFILQAVSA HEKQMREQAKKMN--VASLRSAEAAN---TSA-EAKLAK VALMTISLWFMAWTPY
LWS_schGre  YLLPLGTIIYSYFFILQAVSA HEKQMREQRKKMN--VASLRSAEASQ---TSA-ECKLAK VALMTISLWFFGWTPY
LWS_meoOer  YIGPLALIIYCYFHIVSAVAT HEKQMRDQAKKMG--VKSLRTEEAKK---TSA-ECRLAK VALTTVSLWFMAWTPY
LWS_neoOer  YIGPLALIIYCYFHIVSAVAT HEKQMRDQAKKMG--VKSLRTEEAKK---TSA-GCRLAK VALTTVSLWFMAWTPY
LWS_camLud  YFLPLAITIYCYVFIIKAVAA HEKGMRDQAKKMG--IKSLRNEEAQK---TSA-ECRLAK IAMTTVALWFIAWTPY
LWS_proMil  YFLPLTITIYCYVFIIKAVAA HEKGMRDQAKKMG--IKSLRNEEAQK---TSA-ECRLAK IAMTTVALWFIAWTPY
LWS_eupSub  YLFPFFIIVYCYTYIVSAVFA HEKGMRDQAKKMG--VKSLRNEEAQK---TSA-ECRLAK VALVTVSLWFIAWTPY
LWS_homGam  YFLPLVIIVYCYTYIVAAVSA HERQMREQAKKMG--VKSLRSEESKK---TSN-ECRLAK VALTTVSLWFIAWTPY
LWS_arcGre  YYTPLLYIIYAYTFIVQAVSA HEKGMREQAKKMG--VKSLRNEEAQK---TSA-ECRLAK VALMTVSLWFMAWTPY
LWS_holCos  YLFPLAYIIYSYTFIVKAVAA HEKGMREQAKKMG--VKSLRSEEAQK---TSA-ECRLCK VALMTVTLWFMAWTPY
LWS_neoAme  YIFPLFLNIYLYTFIIKAVAN HEKQMREQAKKMG--VKSLRSEESQK---TSA-ECRLAK VALMTVSLWFMAWTPY
LWS_mysDil  YFIPLGITIYCYSYIVHAVAN HEKSMKEQAKKMG--VKSFRNEETQR---TSA-EFRLAK IALMTVSLWFIAWTPY
LWS_pedHum  YFLPLFIIIYSYIFIIQAVID HENNMRMQAKKME--VASLRSQDDKK---KSV-EIKLAK IALMTIALWFFAWTPY
RH6_droMel  YLTPLLTIIFSYWHIMKAVAA HEKAMREQAKKMN--VASLRNSEADK---SKAIEIKLAK VALTTISLWFFAWTPY
MWS_limPol  YALPLMVIIYCYIFIVKAVCD HERHLREQAKKMN--VASLRSNVDTQ---KASAEMRIAK VALVNVLLWVVSWTPY
BCR_limPol  YALPLMVIIYCYIFIVKAVCD HERHLREQAKKMN--VASLRSNVDTQ---KASAEMRIAK VALVNVLLWVVSWTPY
BCR_dapPul  YCVPLIIIIFCYYHIVRAIVH HEDALRDQAKKMN--VSSLRSNADQK---SQSAEIRVAK IAMMNITLWVAAWTPY
LWS_limPol  YFLPLITMIYCYFFIVHAVAE HEKQLREQAKKMN--VASLRANADQQ---KQSAECRLAK VAMMTVGLWFMAWTPY
LWS2_plePa  YFIPLFTLIYNYTFIVRAVSI HEDNLREQAKKMN--VTSLRANADQQ---KQSAECRLAK IALMTVGLWFIAWTPY
LWS2_hasAd  YFTPLFTLIYNYTFIVRSVSI HENNLREQAKKMN--VSSLRANADQQ---KQSAECRLAK IALMTVGLWFIAWTPY
LWS_ixoSca  YWTPLFINIYCYSKIVRAVAQ HEKQLRLQARKMN--VASLRANAEQT---KTSAEARLAK IALMTVGLWFMAWTPY
LWS1_plePa  YFVPLFIIIYCYTYIVMQVAA HEKSLREQAKKMN--IKSLRSNEDNK---KASAEFRLAK VALMTICLWFMAWTPY
LWS1_hasAd  YFVPLFIIIYCYAFIVMQVAA HEKSLREQAKKMN--IKSLRSNEDNK---KASAEFRLAK VAFMTICCWFMAWTPY
MWS_hemSan  FFLPASVIVFSYVFIVKAIFA HEAAMRAQAKKMN--VTNLRSNEAET---QRA-EIRIAK TALVNVSLWFICWTPY
RH3_droMel  FVCPTTMITYYYSQIVGHVFS HEKALRDQAKKMN--VESLRSNVDKN---KETAEIRIAK AAITICFLFFCSWTPY
RH4_droMel  FVCPTLMILYYYSQIVGHVFS HEKALREQAKKMN--VESLRSNVDKS---KETAEIRIAK AAITICFLFFVSWTPY
UVV_camAbd  YCVPMLLIIYYYSQIVGHVVS HEKALREQAKKMN--VESLRSNVNTN---AQSAEIRIAK AAITICFLFVLSWTPY
UVV_catBom  YCIPMSLIIYYYSQIVSHVVN HEKALREQAKKMN--VESLRSNTNTN---AQSAEIRIAK AAITICFLFVLSWTPY
UVV_apiMel  YCIPMILIIYYYSQIVSHVVN HEKALREQAKKMN--VDSLRSNANTS---SQSAEIRIAK AAITICFLYVLSWTPY
UVV_rhoPro  YVIPMSLIIYFYSQIVSHVII HEHNLREQAKKMN--VESLRSNANMH---TQSAEIRIAK AAITICFLFVASWTPY
UVV_manSex  YVFPMSLIIYFYSGIVKQVFA HEAALREQAKKMN--VESLRANQGGS---SESAEIRIAK AALTVCFLFVASWTPY
UVV_papXut  YIFPMIAILYFYSGIVKQVFA HEAALREQAKKMN--VDSLRSNQNAA---AESAEIRIAK AALTVCFLYVASWTPY
UVV_pedHum  YVLPLSLIIYFYTKIVLHVIN HEKSLKAQAKKMN--VESLRSDGNKN----YAVEIRITK VAIAMCFLFVISWTPY
UVV_dapPul  YVIPLAMLIFYYSKIVRSVGD HEKTLRDQAKKMN--VTSLRSNRDQN---EKSAEVRIAK VAIALATLFVFAWTPY
BLU_manSex  YCIPMALICYFYSQLFGAVRL HERMLQEQAKKMN--VKSLASNKEDN---SRSVEIRIAK VAFTIFFLFICAWTPY
BLU_apiMel  YVIPLIFIILFYSRLLSSIRN HEKMLREQAKKMN--VKSLVSN-QDK---ERSAEVRIAK VAFTIFFLFLLAWTPY
RH5_droMel  YVIPMTMILVSYYKLFTHVRV HEKMLAEQAKKMN--VKSLSANANAD---NMSVELRIAK AALIIYMLFILAWTPY
UVV_plePay  WFIPVAAIVFFYVQIFLAVKD HEEKIKEQARKMN--VDSIRSNEAVK---NSSAEVRIAK TAMCVFLMFLSSWAPY
UVV_hasAda  WFIPVAAIIFFYAQIFLAVKD HEEKIKEQARKMN--VDSFRSNEALK---NSSAEVRIAK TAMCVVLLFLTSWVPY
MEL_plaDum  FIFPVAIIFFCYLGIVRAIFA HHAEMMATAKRMG--A-N--TGKADA---DKKSEIQIAK VAAMTIGTFMLSWTPY
MEL_lotGig  FVVPLGVIIFCYVFIIKSVMN HEKEMAKMADKLD--AKD--VRSTKE---KAKAEIKIAK VSMTIILLYLMSWTPY
MEL_sepOff  FCFPILIIFFCYFNIVMAVSN HEKEMAAMAKRLN--AKE--LRKAQA---GASAEMKLAK ISIVIVTQFLLSWSPY
MEL_todPac  FFGPILIIFFCYFNIVMSVSN HEKEMAAMAKRLN--AKE--LRKAQA---GANAEMRLAK ISIVIVSQFLLSWSPY
MEL_entDof  FMLPIIIIAFCYFNIVMSVSN HEKEMAAMAKRLN--AKE--LRKAQA---GASAEMKLAK ISMVIITQFMLSWSPY
MEL_schMed  FIIPVGIIIFCYYQIVKAVRV HELEMLKMAQKMN--ASHPTSMKTGA----KKADVQAAK ISVIIVFLYMLSWTPY
MEL_schMan  FLCPVFIIIFSYYQIVKTVRL NELELMKMAQSLD--LQNPSAMKTGG---DKKADIEAAK TSIILVLLYLMSWSPY
MEL_patYes  FLIPLIIIGVCYVLIIRGVRR HDQKMLTITRS----MKTEDARANNK---RARSELRISK IAMTVTCLFIISWSPY
<span style="color: #0066CC;">MEL_homSap  FFLPLLIIIYCYIFIFRAIRE TGRALQTFGAC----KGNGESLWQRQ---RLQSECKMAK IMLLVILLFVLSWAPY
MEL_rheMac  FFLPLLIIIYCYIFIFRAIRE TGRALQTFGAC----KGSGESLWQRQ---RLQSECKMAK IMLLVILLFVLSWAPY
MEL_bosTau  FFLPLLIIIYCYIFIFKAIRE TGQALQTFGTC----EGGSECPRQRQ---RLQNEWKMAK IELLVILLFVLSWAPY
MEL_proCap  FFLPLLVIIYCYVFIFKAIRE TGRALQTFGAC----EGASETPRQWQ---RLQSEWKMAK IALLAILLYVLSWAPY
MEL_galGal  FFIPLIAIIYSYVFIFEAIKK ANKSVQTFGCK----HGNRELQKQYH---RMKNEWKLAK IALIVILLYVISWSPY
MEL_monDom  FFIPLIVIIYCYIFIFRAIQD TNKAVHSIGSG-----ESTASPRHCQ---RMKNEWKMAK IALVVILLYVLSWAPY
MEL_xenTro  FFIPLFIIIYCYIFIFKAIKN TNRAVQKIGTD-----NNKESHKQYQ---KMKNEWKMAK IALIVILLYVVSWSPY
MEL_danRer  FFIPLIVIIYCYFFIFRSIRT TNEAVGKINGD-----NKRDSMKRFQ---RLKNEWKMAK IALIVILMYVISWSPY
MEL_gasAcu  FFLPLFIIIYCYFFIFRAIRV TNRAVGKMNGSIHSHGSGRDSTKNFH---RLQNEWKMAK IALIVILLYVVSWSPY
MEL_braFlo  YFIPMGVIIYCYYNIFATVKS GDKQFGKAVKEMAHE-DVKNKAQQER---QRKNEIKTAK IAFIVITLFLSAWTPY
MEL_strPur  FVVPVTIIIVCFTRIAITVRA HRHELNKMRTKLTEDKDKKHKSSIRR-ANKAKTEFQIAK VGFQVTIFYVLSWMPY</span>
MEL_dapPul  FFLPVSVLTFCYAAIFRFILR SSKEITRLIMTSDGTTSFSKSTVSFR-KRRRQTDVRTAL IILSLAILCFTAWTPY
BLU_dapPul  WVCPLTIITFCYAAIVRAVYR VRQNVTRV---PSQPIDNKHLHQCIN---QPNVEIAIPK IVAGLVLSWIIAWTPY
MEL2_schMa  FLCPLFLSLFCYARIILIVRS RGKDFIEM---AASSKGTNQKEKSAN-VSSSKSDTFVSK SSAILLGVYLICWTPY
MEL3_schMa  FMFPVLLCIYCYVNLLKIVRN NERVVLIS---LSNDGASKQRESVRN---RKRLDIEATK SVILSLLFYLMSWTPY
MEL_aplCal  FVLPFALMVFSYFRIWVAVRK VKSGNVFCAIRHNYNLALGSTLFVKQHRYRLHCEQKTVK IIMFLLIAFTVSWSPY
MEL2_lotGi  FVLPLCFILFAYSRILHLISS HSR--EMKSYRSAVIISKGKASIPKRFR----SERKTAI TLLITVVVFCLSWVPY
MEL_helRob  FGMPVSVIILSYIGIIRSIAK NRKEFSSLTAENSS---------------RARQEIKIAK VFAVCMTAFILCWVPY
<span style="color: #990099;">RH7_droMel  YCIPLTSIVYSYFYILKVVFT ASRIQS-----NKD---------------KAKTEQKLAF IVAAIIGLWFLAWSPY
RH7_droYak  YCIPLTSIVYSYFYILKVVFT ASRIQS-----NKD---------------KAKTEQKLAF IVAAIIGLWFLAWSPY
RH7_droPse  YCVPLTTIVYSYFYILKVVFT ASRIQS-----NKD---------------KAKTEQKLAF IVAAIIGLWFLAWSPY
RH7_droGri  YCIPLTCIVYSYFYILKVVFT ANRIQS-----SKD---------------KAKTEQKLTF IVAAIIGLWFIAWSPY</span>
UVV_ixoSca  WCVPLVFVTTCYSGILVTVIR SRKALA-----QES---------------R-RSELRVAK VSLALVLLWTVAWTPY
<span style="color: #FFBB66;">MEL_acrMil  YFVPLAIIVYCYVFMIRSVRF MTKNAQKIW--------GVRSAAALE---TVQATWKMAK IGLIMVVGFFVAWTPY</span>
(continued shortly)


== The carboxy-terminal tail and VxPx motif ==
== The carboxy-terminal tail and VxPx motif ==


This distinctive region has quite baffling length variation across -- and sometimes within -- opsin classes. The extent of conservation also differs greatly, with no real universally conserved residues past the end of the seventh transmembrane helix. The observed terminal conservation pattern for a given opsin must be indicative of its functional importance, even as that stands today insufficiently explained by arrestin phosphoserine or cysteine palmitylation sites, opsin dimerization or other membrane macro organization, or interaction with Galpha proteins. Some interactions would seem to require commonality across all orthology classes (or larger assemblages such as ciliary opsins) while others do not.
This distinctive region has quite baffling length variation across -- and sometimes within -- opsin classes. The extent of conservation also differs greatly, with no real universally conserved residues past the end of the seventh transmembrane helix. The observed terminal conservation pattern for a given opsin must be indicative of its functional importance, even as that stands today insufficiently explained by arrestin phosphoserine or cysteine palmityolation sites, opsin dimerization or other membrane macro organization, or interaction with Galpha proteins. Some interactions would seem to require commonality across all orthology classes (or larger assemblages such as ciliary opsins) while others do not.


Several studies have implicated the carboxy terminal motif VxPx of ciliary opsins as the intra-cellular targeting motif for proteins that function within cilia (or modified apical cilia such as rod and cone outer segments). The phylogenetic origin or age of this motif function has not been established nor its lineage-specific variations, though cilia themselves are pre-metazoan and the need to direct opsins specifically to outer segments would have been present already prior to lamprey divergence.
Several studies have implicated the carboxy terminal motif VxPx of ciliary opsins as the intra-cellular targeting motif for proteins that function within cilia (or modified apical cilia such as rod and cone outer segments). The phylogenetic origin or age of this motif function has not been established nor its lineage-specific variations, though cilia themselves are pre-metazoan and the need to direct opsins specifically to outer segments would have been present already prior to lamprey divergence.


The description of the recognition pattern as VxPx is unsatisfactory. First, it is too short and vapid to serve this purpose. The residues valine and proline are all but inert and valine would be hard for the recognition apparatus to distinguish from leucine and isoleucine. Valine and proline would occur by random in this pattern in 4 proteins per thousand; mis-targeting would arise frequently from de novo substitutions in situations where one of V or P was already present.
The description of the recognition pattern as VxPx alone is unsatisfactory: it is too short and vapid to serve this purpose. The residues valine and proline are all but inert and valine would be hard for the recognition apparatus to distinguish from leucine and isoleucine. Valine and proline would occur by random in this pattern in 4 proteins per thousand; mis-targeting would arise frequently from de novo substitutions in situations where one of V or P was already present. Thus the motif must reflect the end-of-gene position, ie VxPx* properly describes the motif and internal VxPx cannot.


In opsins, we see from cytoplasmic tail alignments below that RGR, persopsin, neuropsins, melanopsins, PPINb and TMT all lack any sign of a terminal VxPx motif. Here TMT is surprising in its total lack of any distal conservation whereas its nearest relative encephalopsin does have a strongly conserved VxPA motif VxPL, x:RK). RHO1 (VAPA), RHO2 (VSPA), SWS2 (VxPy, x:SAG, y:AS), LWS (VxPA X:AS), PPIN (VxPy x:AS, Y:ASLV), PARIE (VxPy x:AST, y:AVL), PIN VxPy x:MTA, y:AS), and VAOP (VxPy x:CY, y:ILM; motif lost in Aves).  
In opsins, we see from cytoplasmic tail alignments below that RGR, peropsin, neuropsins, melanopsins, PPINb and TMT all lack any sign of a terminal VxPx motif. Here TMT is surprising in its total lack of any distal conservation whereas its nearest relative encephalopsin does have a strongly conserved VxPA motif VxPL, x:RK). RHO1 (VAPA), RHO2 (VSPA), SWS2 (VxPy, x:SAG, y:AS), LWS (VxPA X:AS), PPIN (VxPy x:AS, Y:ASLV), PARIE (VxPy x:AST, y:AVL), PIN VxPy x:MTA, y:AS), and VAOP (VxPy x:CY, y:ILM; motif lost in Aves).  


Thus the motif is really quite constrained in second and fourth position to a non-bulky uncharged side chain; VxPx does not accurately describe the observed reduced alphabet at these positions. However the carboxy terminus might have other functionalities in addition to cilial targeting at least in opsins. Conversely it is not so clear that PPIN, PIN, PARIE, VAOP and encephalopsin are specifically targeted to modified pineal, brain, and melanocyte cilia in the same sense that rod and cone opsins are.
Thus the motif is really quite constrained in second and fourth position to a non-bulky uncharged side chain; VxPx does not accurately describe the observed reduced alphabet at these positions. However the carboxy terminus might have other functionalities in addition to ciliary targeting at least in opsins. Conversely it is not so clear that PPIN, PIN, PARIE, VAOP and encephalopsin are specifically targeted to modified pineal, brain, and melanocyte cilia in the same sense that rod and cone opsins are.


Photoreceptor retinol dehydrogenase RDH8, another enzyme of the cis-retinal regeneration cycle located in the outer segments, also terminates in a similar motif VRPR. This is not the case for RDH11, RDH12 or RDH16 [http://www.jneurosci.org/cgi/content/full/24/11/2623 nor] in arrestin, transducin subunits, cGMP phosphodiesterase subunits, cGMP-gated channel subunits, Na/K/Ca exchanger, RGS9, R9AP, guanylate cyclases 2D and 2F, guanylate cyclase activating protein, phosducin, and recoverin.
Photoreceptor retinol dehydrogenase RDH8, another enzyme of the cis-retinal regeneration cycle located in the outer segments, also terminates in a similar motif VRPR. This is not the case for RDH11, RDH12 or RDH16 [http://www.jneurosci.org/cgi/content/full/24/11/2623 nor] in arrestin, transducin subunits, cGMP phosphodiesterase subunits, cGMP-gated channel subunits, Na/K/Ca exchanger, RGS9, R9AP, guanylate cyclases 2D and 2F, guanylate cyclase activating protein, phosducin, and recoverin.


=== RGR ===
=== RGR ===
The first hand-gapped alignment below illustrates these issues using RGR from 53 species. The alignment begins inside the last transmembrane segment with the Schiff base lysine K and continues past the NAxxY motif at a deeply invariant length (totallying 19 residues) to the "YR" motif found in almost all GPCR. This marks the beginning of the carboxy terminal cytoplasmic tail, which in RGR is fairly fixed at 23 residues, remain alignable and may extend the transmembrane helix but bear no resemblance to any other opsin or GPCR.  
The first hand-gapped alignment below illustrates these issues using RGR from 53 species. The alignment begins inside the last transmembrane segment with the Schiff base lysine K and continues past the NAxxY motif at a deeply invariant length (totaling 19 residues) to the "YR" motif found in almost all GPCR. This marks the beginning of the carboxy terminal cytoplasmic tail, which in RGR is fairly fixed at 23 residues, remain alignable and may extend the transmembrane helix but bear no resemblance to any other opsin or GPCR.  


The degree of conservation establishes selection is at work. It appears that RGR must terminate in several charged (characteristically basic) residues irregardless of length indels. These could possibly associate electrostatically with membrane phospholipid or be important to initial establishment of topology. Mammals have in effect lost the YR motif though most have an R one residue later. This does not quite coincide with the advent of ERY or GRY mammals in cytoplasmic loop C2.  
The degree of conservation establishes selection is at work. It appears that RGR must terminate in several charged (characteristically basic) residues regardless of length indels. These could possibly associate electrostatically with membrane phospholipid or be important to initial establishment of topology. Mammals have in effect lost the YR motif though most have an R one residue later. This does not quite coincide with the advent of ERY or GRY mammals in cytoplasmic loop C2.  


Conservation of G.WQ.L..Q has persisted for tens of billions of years and cannot be explained by helix or beta sheet per se -- possibly it is constrained by interaction with parts of the other cytoplasmic face. It appears that arrestin could recognize phospserine or threonine in almost all species but palmityolation cannot be widespread. A few species, such as guinea pig, microbat and armadillo may be exhibiting early stages of pseudogenization or at least partial loss of function.
Conservation of G.WQ.L..Q has persisted for tens of billions of years and cannot be explained by helix or beta sheet per se -- possibly it is constrained by interaction with parts of the other cytoplasmic face. It appears that arrestin could recognize phosphoserine or threonine in almost all species but palmityolation cannot be widespread. A few species, such as guinea pig, microbat and armadillo may be exhibiting early stages of pseudogenization or at least partial loss of function.


Absent any experimental information or relevent 3D structure or capacity for annotation transfer from homologous regions, the specifics of individual residue and residue patch conservation will remain difficult to explain.
Absent any experimental information or relevant 3D structure or capacity for annotation transfer from homologous regions, the specifics of individual residue and residue patch conservation will remain difficult to explain.
               K..PT.NA..YaLG.E.yr .G.Wq.L..q..........k.K     
               K..PT.NA..YaLG.E.yr .G.Wq.L..q..........k.K     
  <font color="blue">>RGR_homSap  KMVPTINAINYALGNEMVC RGIWQCLSPQKRE-----KDRTK  RGR_homSap  KMVPTINAINYALGNEMVC RGIWQCLSPQKREKDRTK       
  <font color="blue">>RGR_homSap  KMVPTINAINYALGNEMVC RGIWQCLSPQKRE-----KDRTK  RGR_homSap  KMVPTINAINYALGNEMVC RGIWQCLSPQKREKDRTK       
Line 452: Line 632:


=== Peropsin ===
=== Peropsin ===
Peropsin exhibits greater conservation both in its post-K helix and in its cytoplasmic tail than RGR. The FR motif is perfectly conserved throughout vertebrates. Length, ancestrally 32 residues, experienced an era of variability in amniotes but then settled down to a fixed 35 residues in mammals. The differance alignment shows that a central motif EITISN conserved in early vertebrates changed character completely (to TMPVTS) in mammals, though the earlier motif still appears faded in platypus. A cysteine conserved back to invertebrates might be palmitoylated; conserved serines and threonines offer potential phosphorylation sites.  
Peropsin exhibits greater conservation both in its post-K helix and in its cytoplasmic tail than RGR. The FR motif is perfectly conserved throughout vertebrates. Length, ancestrally 32 residues, experienced an era of variability in amniotes but then settled down to a fixed 35 residues in mammals. The difference alignment shows that a central motif EITISN conserved in early vertebrates changed character completely (to TMPVTS) in mammals, though the earlier motif still appears faded in platypus. A cysteine conserved back to invertebrates might be palmitoylated; conserved serines and threonines offer potential phosphorylation sites.  


The cytoplasmic tail of peropsin is completely unalignable to RGR. Unlike RGR, tblastn of peropsin tail against whole human genome elicits matches to imaging opsins and a GPCR (neuropeptide Y receptor). While these matches are weak and largely driven by the last transmembrane section alone, 3 early tail residues (*) emerge as possible conserved residues. Whether or not homologically valid, this suggests modeling of the first 9 residues of peropsin tail by known bovine rhodopsin structure.
The cytoplasmic tail of peropsin is completely unalignable to RGR. Unlike RGR, tblastn of peropsin tail against whole human genome elicits matches to imaging opsins and a GPCR (neuropeptide Y receptor). While these matches are weak and largely driven by the last transmembrane section alone, 3 early tail residues (*) emerge as possible conserved residues. Whether or not homologically valid, this suggests modeling of the first 9 residues of peropsin tail by known bovine rhodopsin structure.
Line 603: Line 783:
The cytoplasmic tail in melanopsin can be quite variable in length and sequence. No strongly conserved residues exist in bilateran melanopsins beyond the P.L beginning at position 8; consequently very little can be learned about the cytoplasmic tail of vertebrate or even arthropod melanopsins from study of molluscan melanopsins. Its contribution to structure and function of the cytoplasmic face must be quite variable. Note the FR motif is almost always YR outside of lophotrochozoans.
The cytoplasmic tail in melanopsin can be quite variable in length and sequence. No strongly conserved residues exist in bilateran melanopsins beyond the P.L beginning at position 8; consequently very little can be learned about the cytoplasmic tail of vertebrate or even arthropod melanopsins from study of molluscan melanopsins. Its contribution to structure and function of the cytoplasmic face must be quite variable. Note the FR motif is almost always YR outside of lophotrochozoans.


Within just vertebrates, the cytoplasmic tail of melanopsin exhibits much more extensive conservation of 11 residues extending out to position 66 (human numbering). The two conserved serines might be cyclically phosphorylated and the single cysteine at position 9 palmitoylated (as it cannot be in a disulfide residing in the reduced cytoplasmic mileau).
Within just vertebrates, the cytoplasmic tail of melanopsin exhibits much more extensive conservation of 11 residues extending out to position 66 (human numbering). The two conserved serines might be cyclically phosphorylated and the single cysteine at position 9 palmitoylated (as it cannot be in a disulfide residing in the reduced cytoplasmic milieu).
While the remaining residues are very likely stably structured, it's not clear whether they interact primarily with the other cytoplasmic loops or with auxillary proteins. The latter is more likely recalling that melanopsins signal via Gq and the inositol triphosphate cascade rather than the very different cyclic nucleotide pathway.
While the remaining residues are very likely stably structured, it's not clear whether they interact primarily with the other cytoplasmic loops or with auxiliary proteins. The latter is more likely recalling that melanopsins signal via Gq and the inositol triphosphate cascade rather than the very different cyclic nucleotide pathway.


[[Image:MelCytoTail.jpg|left]]
[[Image:MelCytoTail.jpg|left]]
Line 732: Line 912:
=== Encephalopsin ===
=== Encephalopsin ===


This opsin class, despite its phylogenetically erratic pattern of tetrapod gene loss, is exceedingly conserved in its carboxy terminus in both length and sequence back to cartilaginous fish. An interesting phyloSNP can be seen in the difference alignment in the primate stem (S-->N) two residues after the critical Schiff lysine. This may slightly shift the chemical environment of the chromophore.
This opsin class, despite its phylogenetically erratic pattern of tetrapod gene loss, is exceedingly conserved in its carboxy terminus in both length and sequence back to lamprey. This conservation is unprecedented in this region and must reflect mission-critical binding to another protein.
 
The cytoplasmic tail of encephalopsin has no detectable homology to other ciliary opsins for more that 6 residues beyond the FR motif (FRRSLLQL) even though it shares the same very ancient terminal exon break as other ciliary opsins (phase 0, just prior to the FR). The VxPx* motif can be recognized in the conserved pattern VRPL*; if this primarily drives cell targeting to cilia, it may or may not have arisen independently from similar motifs in other ciliary opsins.


The cytoplasmic tail of encephalopsin has no detectable homology to other ciliary opsins for more that 6 residues beyond the FR motif (FRRSLLQL) even though it shares the same very ancient terminal exon break as other ciliary opsins (phase 0, just prior to the FR).
An interesting phyloSNP can be seen in the difference alignment in the primate stem (S-->N) two residues after the critical Schiff lysine. This may slightly shift the chemical environment of the chromophore.


  ENCEPH_hom KSNTVYNPVIYVFMIRKFR RSLLQLLCLRLLRCQRPAKDLPA-AGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDDSDKT-NGSKVDVIQVRPL   
  ENCEPH_hom KSNTVYNPVIYVFMIRKFR RSLLQLLCLRLLRCQRPAKDLPA-AGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDDSDKT-NGSKVDVIQVRPL   
Line 807: Line 989:
=== TMT opsin ===
=== TMT opsin ===


TMT predominantly exhibits FY for its FR motif though perhaps the conserved FYK/R motif accomplishes the same end. Within the whole TMT family, no observable conservation past the first 9 residues though some 35 residues are alignable within the TMT paralog tracking into tetrapods (up to marsupials). The conserved pair of cysteines might be palmitoylated. Opossum has acquired an upstream stop codon recently as the 22 residues following are still alignable to wallaby. GenBank lacks any transcripts of the main TMT in tetrapods as of Jan 09. This gene is curiously intertwined with the opposing strand gene ST6GAL2, a sialyltransferases in all species.
TMT predominantly exhibits FY for its FR motif though perhaps the conserved FYK/R motif accomplishes the same end. Within the whole TMT family, no observable conservation occurs past the first 9 residues, though some 35 residues are alignable within the sole TMT locus tracking into mammals (marsupials). The conserved pair of cysteines might be palmitoylated. Opossum has acquired an upstream stop codon recently -- the 22 residues following are still alignable to wallaby. GenBank lacks any tetrapod transcripts of this TMT locus as of Jan 09. The last exon of this gene is curiously intertwined with that of the opposing strand gene, the  sialyltransferase ST6GAL2.


  TMT_monDom  KSSTVCNPIIYVLMNKQFY KCFLILFHCQPAQSGPDVS LCPSNVTVIQLGQRKNKDA PGSI*DFPEVSEKQLCLLS PEVWPQP                                         
  TMT_monDom  KSSTVCNPIIYVLMNKQFY KCFLILFHCQPAQSGPDVS LCPSNVTVIQLGQRKNKDA PGSI*DFPEVSEKQLCLLS PEVWPQP                                         
Line 844: Line 1,026:
The cytoplasmic tails of these opsins begin and end with highly conserved motifs but the middle sections have been subject to numerous indels, suggesting that absolute length is unimportant for binding site recognition. The VAPA terminal motif can be recognized in all but the secondary parapinopsin group PPINb (found only in some teleost fish and apparently reflecting differential survival of gene duplication and in avian VAOP where chicken and finch have recent changes in stop codon.
The cytoplasmic tails of these opsins begin and end with highly conserved motifs but the middle sections have been subject to numerous indels, suggesting that absolute length is unimportant for binding site recognition. The VAPA terminal motif can be recognized in all but the secondary parapinopsin group PPINb (found only in some teleost fish and apparently reflecting differential survival of gene duplication and in avian VAOP where chicken and finch have recent changes in stop codon.


LWS is shown [[Opsin_evolution:_LWS_PhyloSNPs#Indels_in_the_cytoplasmic_tail|elsewhere]] greatly expanded to 82 species to illustrate the issues. Four indels, all deletions, have occured during vertebrate history: a 2 residue loss in mammals, a 1 residue loss in birds but not lizards, and a 1 and 5 residue loss in teleost fish. Otherwise, LWS has been remarkably constant -- its key features and almost every residue past FR were already firmly settled prior to lamprey divergence.
LWS is shown [[Opsin_evolution:_LWS_PhyloSNPs#Indels_in_the_cytoplasmic_tail|elsewhere]] greatly expanded to 82 species to illustrate the issues. Four indels, all deletions, have occurred during vertebrate history: a 2 residue loss in mammals, a 1 residue loss in birds but not lizards, and a 1 and 5 residue loss in teleost fish. Otherwise, LWS has been remarkably constant -- its key features and almost every residue past FR were already firmly settled prior to lamprey divergence.


This region cannot be important to Galpha binding because it is too highly variable just within cone opsins which all use the same transducin. Cysteines are conserved to depth but palmitoylation could be universal exclusive of VAOP. LWS also lacks the distal cysteine (CCGK motif has been LFGK since lamprey stem) found in other ciliary opsins. Serines and threonines (for arrestin) are common but are not a deeply conserved feature.
This region cannot be important to Galpha binding because it is too highly variable just within cone opsins which all use the same transducin. Cysteines are conserved to depth but palmitoylation could be universal exclusive of VAOP. LWS also lacks the distal cysteine (CCGK motif has been LFGK since lamprey stem) found in other ciliary opsins. Serines and threonines (for arrestin) are common but are not a deeply conserved feature.
Line 1,546: Line 1,728:
                                       petMa  DRYLVLTRPLASIGAMSKRRAMYITAAVW 
                                       petMa  DRYLVLTRPLASIGAMSKRRAMYITAAVW 
</pre>
</pre>
'''See also:''' [[Opsin_evolution|Curated Sequences]] | [[Opsin_evolution:_ancestral_introns|Ancestral Introns]] | [[Opsin_evolution:_informative_indels|Informative Indels]] | [[Opsin_evolution:_ancestral_sequences|Ancestral Sequences]] | [[Opsin_evolution:_alignment|Alignment]] | [[Opsin_evolution:_update_blog|Update Blog]]


[[Category:Comparative Genomics]]
[[Category:Comparative Genomics]]

Latest revision as of 23:59, 3 December 2010

See also: Curated Sequences | Ancestral Introns | Informative Indels | Ancestral Sequences | Alignment | Update Blog

Comparative genomics of the cytoplasmic face of GPCR proteins

The cytoplasmic face of an opsin (or any GPCR) is comprised of three disjoint connecting loops and the carboxy terminus. It is presumably responsible for all interactions with downstream signal relaying partners because these latter are cytoplasmic proteins having no physical access to the extracellular loops or transmembrane segments. Here it must be noted that photoisomerization and retinal release from Schiff base deep within the transmembrane region must drive a significant change in conformation in the cytoplasmic face that differentiates its inactive from active states.

For bioinformatic purposes, it is convenient to 'reorganize' each linear protein sequence into its intracellular, membrane and outer regions for separate consideration. This is done below for the cytoplasmic face for 500 curated opsins from each of the 20 vertebrate opsin genetic loci using multiple representatives for each phylogenetic node and intense bracketing at eras of functional transition (eg between DRY and GRY opsins of RGR class). A range of non-opsin GPCR are included to define properties common to all members of this large gene family (not specific to opsins).

The two critical goals in GPCR research are finding the natural ligands (which largely concerns the extracellular and transmembrane regions) notably for orphan receptors and to determining their specific Galpha signaling partner among the 17 such paralogs in the vertebrate genome. For vertebrate opsins, the ligand is known (11-cis retinal or related) but the signaling partner generally is not. For example, does RGR opsin signal at all (most are predicted to signal with both Gi/o and Gq/11), to what regulatory effect, and what is the meaning of the abrupt shift in the DRY motif to GRY at boreoeuthere divergence? 

           DRY loop motif       transmemb aa 7 9 signaling
ENCEPH_hom ERYIRVVHARVINFSW     AWRAITYIW 16 V A G?
RGR_homSap GRYHHYCTRSQLAWNS     AVSLVLFVW 16 C R G?
RGR2_gasAc DRYHQYCTRQKLFWST     TLTMSAIIW 16 C R G?
RHO1_homSa ERYVVVCKPMSNFRFGENH  AIMGVAFTW 19 C P GNAT1
RHO2_galGa ERYIVVCKPMGNFRFSATH  AMMGIAFTW 19 C P GNAT2
SWS2_ornAn ERFLVICKPLGNLSFRGTH  AIFGCAATW 19 C P GNAT2
PIN_galGal ERYVVVCRPLGDFQFQRRH  AVSGCAFTW 19 C P G?
SWS1_homSa ERYIVICKPFGNFRFSSKH  ALTVVLATW 19 C P GNAT2
LWS_homSap ERWMVVCKPFGNVRFDAKL  AIVGIAFSW 19 C P GNAT2
VAOP_galGa ERYIVICRPVGNMRLRGKH  AAQGIAFVW 19 C P Gt
PARIE_utaS ERYNVVCQPLGTLQMSTKR  GYQLLGFIW 19 C P Gd+Go
PPIN_xenTr DRVFVVCKPMGTLTFTPKQ  ALAGIAASW 19 C P Gt
PER_homSap DRYLTICLPDVGRRMTTNT  YIGLILGAW 19 C P Go
NEUR1_homS DRYLKICYLSYGVWLKRKH  AYICLAAIW 19 C L G?
NEUR2_galG VCCLKICFPAYGNRFRRKH  GQILIACAW 19 C P G?
NEUR3_galG IRFLVTNSSKSNSNKISKNT VHILITFIW 20 N S G?
NEUR4_ornA TRYIKGCHPHRGHFINTAN  ISVALILIW 19 C P G?
TMT_monDom ERYRTL-TLCPGQGADYQK  ALLAVAGSW 19 - L G?
MEL1_homSa DRYLVITRPLATFGVASKRR AAFVLLGVW 20 T P Gq
MEL2_anoCa DRYCVITKPLQSIKRTSKKR TCIIIVFVW 20 T P Gq

While it might seem straightforward to thread any opsin onto its best fit among the five newly available crystallographic structures, that does not work for distantly related paralogs beyond the universal 7-transmembrane feature because loop regions can be of quite different length and so lack discernible alignability, having diverged greatly in amino acid sequence (even though they are all ultimately homologous).

While these structures entail various compromises (such as replacements of C3 by lysozyme and deletion of carboxy tail to enable stable crystallization), they are hugely important to annotation transfer of sequence/function relationships via comparative genomics. Yet most of the 18 vertebrate opsin orthology classes have only remote models to date and even these can be indeterminate for mid-loop C2 residues (indicative of flexible conformation). 

Gene           PDB            Protein                     PubMed      Best human opsin   Next Best         Signaling

RHO1_bosTau    1JFP 3C9M 2J4Y bovine rod rhodopsin        17825322  RHO1_homSap 93%   SWS1_homSap   45%  Gt GNAT1 raises cGMP
MEL1_todPac    2Z73 2ZIY      squid melanopsin            18480818  MEL1_homSap 43%   PER1_homSap   30%  Gq GNAQ? inositol trisphosphate
ADORA2A_homSap 3EML           adenosine receptor 2A       18832607  MEL1_homSap 27%   ENCEPH_homSap 27%  Gs GNAT3 raises cAMP
ADRB1_melGal   2VT4           beta 1 adrenergic receptor  18594507  MEL1_homSap 29%   ENCEPH_homSap 25%  Gs GNAT3 raises cAMP
ADRB2_homSap   2R4R           beta 2 adrenergic receptor  17962520  MEL1_homSap 28%   PER1_homSap   29%  Gs GNAT3 raises cAMP

It has not proven feasible to predict loop conformations ab initio or from peptide libraries; it is folly to consider individual loop structure in isolation (rather than the cytoplasmic face in its entirety) or fail to specify the activation state being computed. Any predicted structure and special roles for individual residues must be consistent with the comparative genomics of close and even distant orthologs because binding relationships to Galpha and other proteins do not change rapidly in evolutionary time (as seen from heterologous substitution experiments). Even when a cytoplasmic loop seems to lack a definable structure, individual residues can be conserved over vast branch length times. That conservation must ultimately be explained.

OpsinCyto3D.jpg

Two new high resolution structures of squid melanopsin establish that the cytoplasmic face is not structurally homologous even within melanopsins. We knew this already from comparative genomics alignment but not specifically why. The xray structure exhibits unprecedented rigid extensions of transmembrane helices 5 and 6 of order 25 angstroms out into the cytoplasm, greatly constraining the intermediate residues of cytoplasmic loop C3. The proximal carboxy terminus also contributes importantly to the overall structure here.

This structure cannot be replicated in non-cephalopod melanopsins because conservation is observed only out to a proline 8 within the 127 residue FR motif. Even central conservation rapidly drops below 45% even within other lophotrochozoans. Consequently the 25 angstrom cytoplasmic knob of squid melanopsin has no value for annotation transfer but rather represents a lineage-specific innovation. Thus it likely has very little to do with Galpha signaling specificity.

The squid melanopsin structure, submitted online to SwissModel, could otherwise predict the structure of the cytoplasmic loops of all opsins of melanopsin class, of which 48 vertebrate sequences, 9 lophotrochozoan, 43 arthropod, and 1 cnidarian sequences are available here.

The Gq signalling partner will be used throughout these melanopsins, yet what features the Galpha protein specifically recognizes in the cytoplasmic face remain obscure. It cannot really be the terminal helical extension per se because squid Gq protein will prove structuraly homologous to its 16 paralogs (in vertebrates) of different signaling types, meaning some universally conserved feature must be utilized instead.


The first cytoplasmic loop

This can be defined from bovine RHO1 and squid melanopsin structures or by bioinformatic calculation of transmembrane helices. Note the three online tools for that seldom agree with each other or xray structures (which have interpretive artifacts of their own). Here best representatives for each opsin class were found by blastp against SwissProt and the cytoplasmic loop taken from SwissProt annotation. It emerges that that a highly GPCR-conserved glutamate in transmembrane helix 2 must be a fixed number of residues in (namely 10) to conserve its helical wheel position with respect to the overall membrane structure and residues with which it interacts. This aspartate is known to hydrogen bond to Asn55 on TM1 (GFPIN) and main chain Ala299 in TMH7 (AKTSA), thus organizing the relationship of TM1,2,7 in the vicinity of the Schiff base.

Consequently, cytoplasmic loop 1 must end at the PLN motif of RHO1 and hence all other opsins. The beginning of the cytoplasmic loop can be defined by similar considerations. It emerges from a mega-alignment that every opsin is indel-free in this region. Thus all CL1 must be of the same length (12 amino acids). Some sequence conservation, notably the proline at position 9, is universal. This proline may break the continuation of membrane alpha helix from the cytoplasmic domain into the cytoplasm. Internal basic residues are also found consistently.

The question of Galpha binding here must address how opsins using different signaling partners could still be so similar across orthology classes, yet have a fair amount of variation within. 

SwissProt predictions
RHO1_homSa	TVQHKKLRTPLN
SWS1_homSa	TLRYKKLRQPLN
ENCEPH_hom	YYKFQRLRTPTH
TMT_monDom	FCKFKVLRNPVN
MEL1_homSa	FCRSRSLRTPAN
PER1_homSa	FIKYKELRTPTN

Alignment of CL1 (with early residues of TM2 also shown up to the registration residue D)

RHO1_homSa TVQHKKLRTPLN YILLNLAVAD
RHO1_monDo TIQHKKLRTPLN YILLNLAIAD
RHO1_bosTa TVQHKKLRTPLN YILLNLAVAD
RHO1_conMy TIEHKKLRTPLN YILLNLAVAD
RHO1_ornAn TIQHKKLRTPLN YILLNLAFAN
RHO1_angAn TIEHKKLRTPLN YILLNLAVAN
RHO1_galGa TIQHKKLRTPLN YILLNLVVAD
RHO1_neoFo TVQHKKLRTPLN YILLNLAVAD
RHO1_takRu TVKHKKLRTPLN YVLLNLAVAD
RHO1_leuEr TIQHKKLRQPLN YILLNLAVSD
RHO1_calMi TFEHKKLRQPLN FILLNLAVAD
RHO2_calMi TVKHKKLRQPLN FILLNLAVAD
RHO1_latCh TIQHKKLRTPLN YILLDLAVAD
RHO1_anoCa TIQHKKLRTPLN YILLNLAVAN
RHO1_petMa TVQHKKLRTPLN YILLNLAVAN
RHO1_letJa TVQHKKLRTPLN YILLNLAMAN
RHO1_geoAu TVQHKKLRTPLN YILLNLAVSN
RHO1_xenTr TIQHKKLRTPLN YILLNLVFAN
RHO2_galGa TFKHKKLRQPLN YILVNLAVAD
RHO2_podSi TFKHKKLRQPLN YILVNLAVAD
RHO2_anoCa TFKHKKLRQPLN YILVNLAVAD
RHO2_taeGu TFKHKKLRQPLN YILVNLAVAD
RHO2_neoFo TFKHKKLRQPLN YILVNLAVAD
RHO2_latCh TFKHKKLRQPLN YILVNLAVAS
RHO2_gekGe TFQHKKLRQPLN YILVNLAAAN
RHO2_pheMa TFQHKKLRQPLN YILVNLAVAN
RHO2_geoAu TFKLKKLRQPLN FILVNLCVAD
RHO2_ancDa TAQHKKLRQPLN FILVNLAVAG
RHO2d_danR TAQHKKLRQPLN FILVNLAVAG
RHO2c_danR TAQHKKLRQPLN FILVNLAVAG
RHO2a_danR TAQHKKLRQPLN YILVNLAFAG
RHO2b_danR TAQHKKLRQPLN YILVNLAFAG
RHO2_oryLa TAQNKKLRQPLN FILVNLAVAG
RHO2_takRu TAQNKKLRQPLN YILVNLAVAG
RHO2_gasAc TAQNKKLRQPLN YILVNLAVAG
RHO2_oreNi TAQNKKLRQPLN YILVNLAVAG
RHO2_hipHi TAQNKKLRQPLN YILVNLAVAG
RHO2_mulSu TFQNKKLQQPLN YILVNLAVVG
RHO2_pomMi TFQNKKLRQPLN FILVNLAVAG
SWS2_ornAn TIKYKKLRSHLN YILVNLAVSN
SWS2_anoCa TFKYKKLRSHLN YILVNLSVSN
SWS2_utaSt TFKYKKLRSHLN YILVNLAVSN
SWS2_taeGu TAKYKKLRSHLN YILVNLAVAN
SWS2_neoFo TFKYKKLRSHLN YILVNLAVAN
SWS2_xenTr TVKYKKLRSHLN YILVNLAVAN
SWS2_galGa TARFRKLRSHLN YILVNLALAN
SWS2_geoAu TIKYKKLRSHLN YILVNLAIAN
SWS2_takRu TIQYKKLRSHLN YILVNLAFSN
SWS2_gasAc TVQNKKLRSHLN YILVNLAVSN
SWS1_homSa TLRYKKLRQPLN YILVNVSFGG
SWS1_monDo TLRYKKLRQPLN YILVNVSLCG
SWS1_smiCr TLRYKKLRQPLN YILVNISLAG
SWS1_tarRo TLRYKKLRQPLN YILVNISLAG
SWS1_anoCa TVKYKKLRQPLN YILVNISFAG
SWS1_utaSt TVKYKKLRQPLN YILVNISFAG
SWS1_neoFo TIKYKKLQQPLN YILVNISLAG
SWS1_taeGu TIKYKKLRQPLN YILVNISVSG
SWS1_xenLa TIKYKKLRQPLN YILVNITVGG
SWS1_galGa TVRYKRLRQPLN YILVNISASG
SWS1_petMa TVKCKKLRQPLT YMLVNISAAG
SWS1_geoAu TIKYKKLRQPLN YILVNISAAG
SWS1_danRe TMKYKKLRQPLN YILVNISLAG
SWS1_oryLa TAKYKKLRVPLN YILVNITFAG
LWS_homSap TMKFKKLRHPLN WILVNLAVAD
LWS_monDom TMKFKKLRHPLN WILVNLAVAD
LWS_ornAna TMKFKKLRHPLN WILVNLAVAD
LWS_galGal TWKFKKLRHPLN WILVNLAVAD
LWS_anoCar TAKFKKLRHPLN WILVNLAIAD
LWS_neoFor TYKFKKLRHPLN WILVNLAIAD
LWS_xenTro TLKFKKLRHPLN WILVNMAIAD
LWS_takRub TAKFKKLRHPLN WILVNLAIAD
LWS_gasAcu TAKFKKLQHPLN WILVNLAIAD
LWS2_calMi TWKFKKLRHPLN WILVNLAIAD
LWS_geoAus TLKFKKLRHPLN WILVNLAIAD
LWS_petMar TVKFKKLRHPLN WIIVNLAIAD
LWS_letJap TMKFKKLRHPLN WILVNLAIAD
LWS1_calMi TVRFKKLRHPLN WILVNMALAD
PIN_galGal SICYKKLRSPLN YILVNLAVAD
PIN_colLiv SIRYKKLRSPLN YILVNLAMAD
PIN_taeGut SVRHKRLRSPLN YILLNLAVAN
PIN_utaSta SIQYKKLRSPLN YILVNLAIAD
PIN_podSic SVQFKKLRSPLN YVLVNLAVAD
PIN_pheMad SVRFKRLRSPLN YILVNLATAD
PIN_xenTro TLKYKKLRSPLN YILVNLAIAN
PIN_bufJap SLKYKKLRSPLN YILVNLAVAD
VAOP_galGa TFKFKQLRQPVN YVIVNLSVAD
VAOP_taeGu TFKFKQLRQPIN YIIVNLSVAD
VAOP_anoCa TIKFKQLRQPLN YVIVNLSVAD
VAOP_danRe TFRFQQLRQPLN YIIVNLSLAD
VAOP_rutRu TFRFTQLRKPLN YIIVNLSLAD
VAOP_takRu TFKFKQLRQPLN YIIVNLAIAD
VAOP_xenTr TAKFKQLRQPLN YIIVNLSVAD
VAOP_petMa TARFRQLRQPLN YVLVNLAAAD
PPIN_anoCa TIKYRQLRQPIN YSLVNLAIAD
PPIN_xenTr TFKYRQLRHPIN YSLVNLAIAD
PPINa_petM TLRHRQLRHPLN FSLVNLAVAD
PPIN_letJa TLRHRQLRHPLN FSLVNLAVAD
PPIN_danRe TLKYKQLRQPLN FALVNLAVAD
PPIN_ictPu TVRYKQLRQPLN YALVNLAVAD
PPIN_oncMy TMRHRKLRQPLN YALVNLAVAD
PPINb_takR TMKHRQLRQPLS YALVNLAICD
PPINb_tetN TLKHRQLRQPLN YALVNLAICD
PPINb_gasA TARHRQLRQPLS YALVNLAVCD
PPINa_gasA TLMHKQLRQPLN YALVNMALAD
PPINa_takR SLMHKQLRQPLN YALVNMAVAD
PPINa_tetN SLMHKQLRQPLN YALVNMAAAD
PPINa_cioI TLKNKVLRQPLN YIIVNLAVVD
PPINa_cioS TLKNKVLRQPLN YIIVNLAVVD
PPINb_cioI TMKNKKLRQPLN YIIINLSIAD
PPINb_cioS TYKNKDLRRPIN YIIVNLAVAD
PARIE_utaS TLKNPQLRNPIN IFILNLSFSD
PARIE_anoC TLKNPQLRNPIN IFILNLSFSD
PARIE_xenT TLKHPQLRNPIN IFILNLSFSD
PARIE_takR MLKNPSLLQPIN IFILSLAVSD
PARIE_tetN MLKNPALLQPIN IFILSLAVSD
PARIE_gasA LVRNPSLLQPMN VFILSLAVSD
PARIE_danR MVKNLHFLNAMT VIIFSLAVSD
ENCEPH_hom YYKFQRLRTPTH LLLVNISLSD
ENCEPH_oto YYKFPRLRTPTH LFLVNISLSD
ENCEPH_lox YYKFQRLRTPTH LFLVNISLSD
ENCEPH_mon YYKFQRLRTPTH LFLVNISFND
ENCEPH_can FLEFQRLRTPTH LLLVNLSLSD
ENCEPH_mus YSKFPRLRTPTH LFLVNLSLGD
ENCEPH_pte YYKFQQVRTPFY LFLVNISFSD
ENCEPH_ano YAKFKRLRTPTH LFLVNISLSD
ENCEPH_gal YYKFKRLRTPTN LFLVNISLSD
ENCEPH_dan YSRYKRLRTPTN LLIVNISVSD
ENCEPH_tak YCRFKRLRTPTN LLLVNISLSD
ENCEPH_ory YCKFKRLRTPTS LLLVNISLSD
ENCEPH_gas YCKFKRLRTPTN LLVVNISLSD
ENCEPH_squ YCKFKRLRTPTN LFLVNISISD
ENCEPH_pet FVGFKRLQTPTN LLLVNISLSD
ENCEPH_cal YYKFKRLRTPTN LLLVNISVSD
ENCEPH_xen YCKFKRLQTPTN LLFFNTSLCH
ENCEPH4_br IGCHRQLRTPFN LLLLNMSVAD
TMT_braFlo FLKFRQLRTPFN MLLLNMSVAD
TMT_braBel FLKFPQLRTPFN LLLLNMAVAD
TMT_monDom FCKFKVLRNPVN MLLLNISISD
TMT_macEug FCKFKVLRNPVN MLLLNISISD
TMT_galGal FCKFKTLRNPVN MLLLNISISD
TMT_anoCar FCKFKTLRNPVN MLLLNISASD
TMT_taeGut FCKFKTLRNPVN MLLLNISVSD
TMT_xenTro FCKFKTLRTPVN MMLLNISASD
TMT_ornAna FCKFKALRNPVN MIMLNISASD
TMT_danRer FCKFKTLRTPVN MLLLNISISD
TMT_takRub FCKFKKLRTPVN MLLLNISVSD
TMT_oryLat FCKFKKLRTPVN MLLLNISVSD
TMT_gasAcu FCKFKKLRTPVN MLLLNISVSD
TMT_tetNig FCKFKKLRTPVN VLLLNISVSD
TMTa1_danR FGRYKVLRSPIN FLLVNICLSD
TMTa_takRu FCRYKMLRSPIN LLLMNISISD
TMTa_tetNi FCRFKVLRSPIN LLLVNISVSD
TMTa_gasAc FCRYKMLRSPIN LLLINISISD
TMTa_oryLa FCRYKILRSPIN LLLINISISD
TMTa_pimPr FCRYKVLRSPMN YLLVSIAVSD
TMTb_danRe FCRYKVLRSPMN CLLISISVSD
TMTa1_calM FCKYKVLRSPMN MLLLNISVSD
TMTb_takRu FCRYRALRTPMN LMLVSISASD
TMTb_tetNi FCRFRALRTPMN LMLVSISASD
TMTb_oryLa FCRYRALRTPMN LLLVSISVSD
TMTb_gasAc FCRYRALRTPMN LLLVSISASD
TMTa_braFl VGRYKQLRTPFN ILMVNLSVSD
MEL2_strPu FLRFKKLHSPIN LLIVNLSASD
MEL1_homSa FCRSRSLRTPAN MFIINLAVSD
MEL1_panTr FCRSRSLRTPAN MFIINLAVSD
MEL1_gorGo FCRSRSLRTPXN MFIINLAVSD
MEL1_ponAb FCRSRGLRTPAN MFIINLAVSD
MEL1_rheMa FCRSRGLRTPAN MFIINLAISD
MEL1_calJa FCRSRGLRTPAN MFIINLAVSD
MEL1_bosTa FCRSRGLRTPAN MFIINLAVSD
MEL1_susSc FCRSRGLRTPAN MFIINLAVSD
MEL1_equCa FCRSRGLRTPAN MFIINLAVSD
MEL1_eriEu FCRSRSLRTPAN MFIINLAVSD
MEL1_echTe FCRSRSLRTPAN MLIINLAVSD
MEL1_otoGa FCRVRGLRTPAN MFVINLAVSD
MEL1_micMu FCRSRSLRTPAN MFVINLAVSD
MEL1_myoLu FCRSRGLRTPAN MFIINLAVSD
MEL1_pteVa FCRSRGLRTPAN MFIINLAVSD
MEL1_felCa FCRSRGLRTPAN MFIINLAVSD
MEL1_canFa FCRTRGLRTPSN MFIINLAVSD
MEL1_proCa FFRSRGLRTPAN MFIINLAISD
MEL1_loxAf FFRSRGLRTPAN MFIINLAVSD
MEL1_musMu FCRNRGLRTPAN MFIINLAVSD
MEL1_ratNo FCRNRGLRTPAN MLIINLAVSD
MEL1_phoSu FCRSRSLRTPAN MLIINLAVSD
MEL1_nanEh FCRSRGLRTRAN MFTVNLAVSD
MEL1_smiCr FCRSRSLRTPAN MFIINLAISD
MEL1_monDo FCRSHSLRTPAN MFIINLAISD
MEL1_xenTr FCRSRSLRSPAN MFIINLAITD
MEL1_ornAn FCRSRSLRTPAN MFIINLSISD
MEL1_taeGu FCRSRSLQTPAN ILIINLAISD
MEL1_galGa FCRSRTLQKPAN IFIINLAVSD
MEL1_danRe FSRSRTLRTPAN LFIINLAITD
MEL1_gasAc FSKSRSLRTPAN MFIINLAITD
MEL1_oryLa FSRSRSLRTPAN MFIINLAITD
MEL1_takRu FCRSRSLRTPAN MFIINLAVTD
MEL1_calMi FLRSRSLRTPAN TFIINLAATD
MEL1_petMa FSKSKSLRSPAN IFIINLAFAD
MEL2_galGa FYSNKKLRTPQN FFIMNLAVSD
MEL2_anoCa FYSNKRLRTPPN YFIMNLAVSD
MEL2_xenLa FYRNKKLRTAPN YFIINLAISD
MEL2_tetNi FYSNKKLRSLPN YFIVNLAVSD
MEL2_danRe FYRNKKLRSLPN YFIMNLAVSD
MEL2_gasAc VYSNKKLRNLPN YFIMNLAVSD
MEL1a_braF FIKSKGLRTPAN FFIINLALSD
MEL1a_braB FIKSKGLRTPAN FFIINLALSD
TMTPIN_sto FARFPSLRHPIN SFLFNVSLSD
PER2_patYe FAKRRSVRRPIN FFVLNLAVSD
PER1_homSa FIKYKELRTPTN AIIINLAVTD
PER1_monDo FVKYKALRTATN TIIINLAVTD
PER1_ornAn FVKFEELRTATN AIIINLAVTD
PER1_xenTr FVKYKELRTATN AIIINLAFTD
PER1_gasAc FWKFKELRTATN FIIINLAFTD
PER1a_braF FTKFRSLRSPTT MLLVHLAIAD
PER1a_braB FSKFRSLRSPTT MLLVHLAIAD
NEUR_strPu SLRKREKLKPID LLTINLAIAD
NEUR1_homS SSRRKKKLRPAE IMTINLAVCD
NEUR1_calJ SSRRKKKLRPAE IMTINLAVCD
NEUR1_canF SSRRKKKLRPAE IMTINLAICD
NEUR1_bosT SSRRKKKLRPAE IMTVNLAICD
NEUR1_dasN SSKRKKKLRPAE IMTINLAVCD
NEUR1_musM SSRRKKKLRPAE IMTINLAVCD
NEUR1_ornA SSRRKKKLRPAE IMTVNLAVCD
NEUR1_loxA SCRRKKKLRPAE IMTINLAVCD
NEUR1_monD SSKRKKKLRPAE IMTVNLAVCD
NEUR1_ochP SSRRKKKLRPAE IMTINLAVCD
NEUR1_galG SSKRKKKLRPAE IMTVNLAVCD
NEUR1_xenT ACSRKKKLRPAE IMTINLAVCD
NEUR1_danR TFKRKTKLKPPE IMTLNLAIFD
NEUR1_calM SITQKRKLKPPE ILITNLAISD
NEUR1a_bra SYRCRARLRPVE MFVVSLAAAD
NEUR1b_bra SYRNWAKLRPVE LFVVSLAVTD
NEUR2_galG SYKKKHLLKPAE YFIINLAISD
NEUR2_anoC SYKKKNLLKPAE YFMINLAISD
NEUR2_xenT AYRKRSILKPAE FFIVNLSISD
NEUR2_danR AYRKRSSLKPAE FFVVNLSVSD
NEUR3_galG AVKRSSLLKSPE LLTVNLAVAD
NEUR3_taeG AVKRSSLLKPPE LLTVNLAVAD
NEUR3_anoC AVKRSSCLRSPE LLTVNLAATD
NEUR3_xenT AVKCSSHLKAPD LLSINLAVAD
NEUR3b_dan AYKRSNHMKPPE LLSVNLAVTD
NEUR3a_dan AAWRHSVLKAPE LLTVNLAVTD
NEUR3a_tet ASRRLTPLKAPE LLTVNLAVTD
NEUR3_petM AARRWAKLKAPE LLSVNLALTD
PER2a_strP RYRTFRKRSINL LLINMAASDL
PER2b_strP RYGTFRKRSVNI LLMNMAVSDL
PER1b_braF WRQLCRKAPNLL IINLAAVDLC
PER1b_braB WRQLCRKAPNLL VINLAAANLC
PER2_braFl TEKEFRKKEHNS FALNLAIADL
PER2_braBe TEKEFRKKQQNG FVLNLAIADL
PER1a_sacK SNPDYCSKAGN- FFLSLAVTDL
RGR1_homSa FCKTPELRTPCH LLVLSLALAD
RGR1_ornAn FRKIKELRTPSN LLVVSLALAD
RGR1_galGa FRKIKELRTPSN LLVLSIALAD
RGR1_xenTr FYKIRELRTPSN LFIISLAVAD
RGR1_gasAc FLKVRELRTPSN FLVFSLAVAD
RGR1_calMi FYKIKELRTPSN LLITSLALSD
RGR2_danRe FLRVREMQTPNN FFIFNLAVAD
RGR2_pimPr FLRVREIQTPNN FFIFNLAVAD
RGR2_tetNi FLTVKEMRNPSN FFVFNLALAD
RGR2_gasAc FLRVKEMWNPSN FFVFNLAVAD
RGR2_oryLa FLRVKEMRSPSS FLVFNLALAD
MEL1b_braF FCRSRSLRRPKN YLIANLCLTD
MEL1b_braB FCRTRSLRRPKN YVVANLCLTD
PER1_lotGi EKGLFKYGRAWL HISLAIANVG
PER1_aplCa DTKLTKGSQPWL HILLALANVG
PER1_todPa ARQSPKPRRKYA ILIHVLITAM
NEUR4_ornA LHRQRGILNPTD YLTFNLAVSD
NEUR4_galG LYKQRHLLQPTD YLTFNLAVSD
NEUR4_taeG LYKQRHVLQPTD YLTFNLAVSD
NEUR4_anoc LYRQRAGLQPTD YLTFNLAVSD
NEUR4_xenT LYKQRANLLPTD YLTFNLAVSD
NEUR4_danR LFRQRSTLQPTD YLTLNLAVSD
NEUR4_tetN LVRQRSSLQPTD LLTFNLAVSD
NEUR4_gasA LYRQRASLQSTD FLTLNLAISD
NEUR4_calM LYRQRLSLQPPD YLTLNLAVSD
MEL1_anoCa FFRIRGLRTPAN MFVINLAVSD

(to be continued)

The second cytoplasmic loop

In squid melanopsin, first six residues of cytoplasmic loop C2 also form an extensional helix in squid melanopsin beginning with the DRY motif and surprisingly terminating three residues before the deeply conserved proline (normally a helix breaker as in adrenergic receptors). This proline alone cannot define the two states through its cis and trans configurations because glycine or leucine can also characterize whole opsin orthology classes at this position. The last 3 residues of basic character HRR of loop C2 also preface a transmembrane helix as RAR do in distantly related turkey adrenergic receptor.

Cytoplasmic loop C2 has conserved length of 16-20 in all opsins with much more rigid constraint within individual opsin classes (eg all vertebrate imaging opsins have length 19. The structure of the C2 loop of over 100 melanopsins can readily be modelled based on its closest match among the determined structures, currently squid melanopsin or bovine rhodopsin, with adenosine and adrenergic receptors serving as 'structural outgroup'.

On the basis of length (19 to rhodopsin, 20 to melanopsin), all the opsins except encephalopsin and RGR (both 16 residues) and TMT (18 residues subsequent to a deletion in amniote stem) have a structural model. This model is further constrained by predictable helical extensions of transmembrane helices into the cytoplasm, leaving only the mid-loop region to be predicted. It's not clear whether observed residue conservation -- both within and across orthology classes -- derives from structural importance or instead to Galpha binding specificity requirements.

The adenosine and adrenergic receptor structures -- however useful they might be for annotation transfer to the other 350 non-oderant human GPCR -- ultimately will not prove helpful in modeling the second cytoplasmic loop of opsins (squid melanopsin does that better already). Note C2 in these three structures is consistently stabilized by a mid-loop hydrogen bond to the DRY residues. This constraint is not observed in squid melanopsins or other metazoan opsin classes; indeed it is not feasible because no hydrogen bond-capable residue consistently occurs there (in the comparative genomics sense of conserved residue). Ancestrally, this mid-loop bridge might be a derived feature fairly early in the stem of non-opsin GPCR.

OpsinCyto2Five.jpg

MelSecStr.jpg


(to be continued)

The third cytoplasmic loop in 83 melanopsins

This loop may be an important contributer to the Gq specificity. The structure has been determined for squid melanopsin, denoted MEL_todPac below. It is a typical 'HEK' extended-helix CL3 found in vast majority of protostome melanopsins. However deuterostome melanopsins never have this feature, yet also appear to signal through Gq. Melanopsin introns within this motif are considered elsewhere.

The orphan Drosophila opsin RH7, which has not yet been associated with an anatomical structure, also lacks the HEK feature and is considerably shorter. However, as the lower sequences in the alignment below show, length variability is by no means unprecedented in this melanopsin loop. Indeed, the one cnidarian opsin available also lacks the HEK motif and also the length of those motifs.

The HEK motif is not specific to wavelength or ommatidia position as the full gamut of drosophila opsins RH1-RH6 have the feature. The motif specifically co-occurs with conserved A.K and more distal A..A whereas a more distal E....K motif are almost universal to all melanopsins -- indeed the E is universal to all opsins (except RGR and peropsin) but not other GPCR. Curiously RH7 has phenylalanine in place of K here. Alanine is inert in terms of side chain potential for interactions, so its conservation is a bit puzzling.

HEKopsin.jpg 

gene        transmembrane helix 5         cytoplasmic loop CL3            transmem helix 5 

RH1_droMel  YYIPLFLICYSYWFIIAAVSA HEKAMREQAKKMN--VKSLRSSEDAE---KSA-EGKLAK VALVTITLWFMAWTPY
RH2_droMel  YYTPLFLICYSYWFIIAAVAA HEKAMREQAKKMN--VKSLRSSEDCD---KSA-EGKLAK VALTTISLWFMAWTPY
LWS1_apiMe  YYTPLFTIIYSYYFIVSAVAA HEKAMKEQAKKMN--VTSLRSGDNQN---TSA-EAKLAK VALTTISLWFMAWTPY
LWS2_apiMe  YFVPLFLIIYSYWFIIQAVAA HEKNMREQAKKMN--VASLRSSENQN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_bomTer  YFFPLFLIIWSYWFIiQAVAA HEKNMREQAKKMN--VASLRSSENQN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_catBom  YFLPLFLIIYSYFFIIQAVAA HEKNMREQAKKMN--VASLRSAENQS---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_papXut  YYTPLLLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSEAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_manSex  YFLPLLLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSEAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_vanCar  YFSPLFLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSDAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_helSar  YYAPLFLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSDAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_pieRap  YFLPLFLIVYSYWFIVQAVAA HERAMREQAKKMN--VASLRSSEQAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_triCas  YFVPLFTIIYSYWFIVQAVAA HEKSMREQAKKMN--VASLRSSEAAQ---TSA-ECKLAK IALMTITLWFFAWTPY
LWS_rhoPro  YFLPLFTIIYSYFFILQAVSA HEKQMREQAKKMN--VASLRSAEAAN---TSA-EAKLAK VALMTISLWFMAWTPY
LWS_schGre  YLLPLGTIIYSYFFILQAVSA HEKQMREQRKKMN--VASLRSAEASQ---TSA-ECKLAK VALMTISLWFFGWTPY
LWS_meoOer  YIGPLALIIYCYFHIVSAVAT HEKQMRDQAKKMG--VKSLRTEEAKK---TSA-ECRLAK VALTTVSLWFMAWTPY
LWS_neoOer  YIGPLALIIYCYFHIVSAVAT HEKQMRDQAKKMG--VKSLRTEEAKK---TSA-GCRLAK VALTTVSLWFMAWTPY
LWS_camLud  YFLPLAITIYCYVFIIKAVAA HEKGMRDQAKKMG--IKSLRNEEAQK---TSA-ECRLAK IAMTTVALWFIAWTPY
LWS_proMil  YFLPLTITIYCYVFIIKAVAA HEKGMRDQAKKMG--IKSLRNEEAQK---TSA-ECRLAK IAMTTVALWFIAWTPY
LWS_eupSub  YLFPFFIIVYCYTYIVSAVFA HEKGMRDQAKKMG--VKSLRNEEAQK---TSA-ECRLAK VALVTVSLWFIAWTPY
LWS_homGam  YFLPLVIIVYCYTYIVAAVSA HERQMREQAKKMG--VKSLRSEESKK---TSN-ECRLAK VALTTVSLWFIAWTPY
LWS_arcGre  YYTPLLYIIYAYTFIVQAVSA HEKGMREQAKKMG--VKSLRNEEAQK---TSA-ECRLAK VALMTVSLWFMAWTPY
LWS_holCos  YLFPLAYIIYSYTFIVKAVAA HEKGMREQAKKMG--VKSLRSEEAQK---TSA-ECRLCK VALMTVTLWFMAWTPY
LWS_neoAme  YIFPLFLNIYLYTFIIKAVAN HEKQMREQAKKMG--VKSLRSEESQK---TSA-ECRLAK VALMTVSLWFMAWTPY
LWS_mysDil  YFIPLGITIYCYSYIVHAVAN HEKSMKEQAKKMG--VKSFRNEETQR---TSA-EFRLAK IALMTVSLWFIAWTPY
LWS_pedHum  YFLPLFIIIYSYIFIIQAVID HENNMRMQAKKME--VASLRSQDDKK---KSV-EIKLAK IALMTIALWFFAWTPY
RH6_droMel  YLTPLLTIIFSYWHIMKAVAA HEKAMREQAKKMN--VASLRNSEADK---SKAIEIKLAK VALTTISLWFFAWTPY
MWS_limPol  YALPLMVIIYCYIFIVKAVCD HERHLREQAKKMN--VASLRSNVDTQ---KASAEMRIAK VALVNVLLWVVSWTPY
BCR_limPol  YALPLMVIIYCYIFIVKAVCD HERHLREQAKKMN--VASLRSNVDTQ---KASAEMRIAK VALVNVLLWVVSWTPY
BCR_dapPul  YCVPLIIIIFCYYHIVRAIVH HEDALRDQAKKMN--VSSLRSNADQK---SQSAEIRVAK IAMMNITLWVAAWTPY
LWS_limPol  YFLPLITMIYCYFFIVHAVAE HEKQLREQAKKMN--VASLRANADQQ---KQSAECRLAK VAMMTVGLWFMAWTPY
LWS2_plePa  YFIPLFTLIYNYTFIVRAVSI HEDNLREQAKKMN--VTSLRANADQQ---KQSAECRLAK IALMTVGLWFIAWTPY
LWS2_hasAd  YFTPLFTLIYNYTFIVRSVSI HENNLREQAKKMN--VSSLRANADQQ---KQSAECRLAK IALMTVGLWFIAWTPY
LWS_ixoSca  YWTPLFINIYCYSKIVRAVAQ HEKQLRLQARKMN--VASLRANAEQT---KTSAEARLAK IALMTVGLWFMAWTPY
LWS1_plePa  YFVPLFIIIYCYTYIVMQVAA HEKSLREQAKKMN--IKSLRSNEDNK---KASAEFRLAK VALMTICLWFMAWTPY
LWS1_hasAd  YFVPLFIIIYCYAFIVMQVAA HEKSLREQAKKMN--IKSLRSNEDNK---KASAEFRLAK VAFMTICCWFMAWTPY
MWS_hemSan  FFLPASVIVFSYVFIVKAIFA HEAAMRAQAKKMN--VTNLRSNEAET---QRA-EIRIAK TALVNVSLWFICWTPY
RH3_droMel  FVCPTTMITYYYSQIVGHVFS HEKALRDQAKKMN--VESLRSNVDKN---KETAEIRIAK AAITICFLFFCSWTPY
RH4_droMel  FVCPTLMILYYYSQIVGHVFS HEKALREQAKKMN--VESLRSNVDKS---KETAEIRIAK AAITICFLFFVSWTPY
UVV_camAbd  YCVPMLLIIYYYSQIVGHVVS HEKALREQAKKMN--VESLRSNVNTN---AQSAEIRIAK AAITICFLFVLSWTPY
UVV_catBom  YCIPMSLIIYYYSQIVSHVVN HEKALREQAKKMN--VESLRSNTNTN---AQSAEIRIAK AAITICFLFVLSWTPY
UVV_apiMel  YCIPMILIIYYYSQIVSHVVN HEKALREQAKKMN--VDSLRSNANTS---SQSAEIRIAK AAITICFLYVLSWTPY
UVV_rhoPro  YVIPMSLIIYFYSQIVSHVII HEHNLREQAKKMN--VESLRSNANMH---TQSAEIRIAK AAITICFLFVASWTPY
UVV_manSex  YVFPMSLIIYFYSGIVKQVFA HEAALREQAKKMN--VESLRANQGGS---SESAEIRIAK AALTVCFLFVASWTPY
UVV_papXut  YIFPMIAILYFYSGIVKQVFA HEAALREQAKKMN--VDSLRSNQNAA---AESAEIRIAK AALTVCFLYVASWTPY
UVV_pedHum  YVLPLSLIIYFYTKIVLHVIN HEKSLKAQAKKMN--VESLRSDGNKN----YAVEIRITK VAIAMCFLFVISWTPY
UVV_dapPul  YVIPLAMLIFYYSKIVRSVGD HEKTLRDQAKKMN--VTSLRSNRDQN---EKSAEVRIAK VAIALATLFVFAWTPY
BLU_manSex  YCIPMALICYFYSQLFGAVRL HERMLQEQAKKMN--VKSLASNKEDN---SRSVEIRIAK VAFTIFFLFICAWTPY
BLU_apiMel  YVIPLIFIILFYSRLLSSIRN HEKMLREQAKKMN--VKSLVSN-QDK---ERSAEVRIAK VAFTIFFLFLLAWTPY
RH5_droMel  YVIPMTMILVSYYKLFTHVRV HEKMLAEQAKKMN--VKSLSANANAD---NMSVELRIAK AALIIYMLFILAWTPY
UVV_plePay  WFIPVAAIVFFYVQIFLAVKD HEEKIKEQARKMN--VDSIRSNEAVK---NSSAEVRIAK TAMCVFLMFLSSWAPY
UVV_hasAda  WFIPVAAIIFFYAQIFLAVKD HEEKIKEQARKMN--VDSFRSNEALK---NSSAEVRIAK TAMCVVLLFLTSWVPY
MEL_plaDum  FIFPVAIIFFCYLGIVRAIFA HHAEMMATAKRMG--A-N--TGKADA---DKKSEIQIAK VAAMTIGTFMLSWTPY
MEL_lotGig  FVVPLGVIIFCYVFIIKSVMN HEKEMAKMADKLD--AKD--VRSTKE---KAKAEIKIAK VSMTIILLYLMSWTPY
MEL_sepOff  FCFPILIIFFCYFNIVMAVSN HEKEMAAMAKRLN--AKE--LRKAQA---GASAEMKLAK ISIVIVTQFLLSWSPY
MEL_todPac  FFGPILIIFFCYFNIVMSVSN HEKEMAAMAKRLN--AKE--LRKAQA---GANAEMRLAK ISIVIVSQFLLSWSPY
MEL_entDof  FMLPIIIIAFCYFNIVMSVSN HEKEMAAMAKRLN--AKE--LRKAQA---GASAEMKLAK ISMVIITQFMLSWSPY
MEL_schMed  FIIPVGIIIFCYYQIVKAVRV HELEMLKMAQKMN--ASHPTSMKTGA----KKADVQAAK ISVIIVFLYMLSWTPY
MEL_patYes  FLIPLIIIGVCYVLIIRGVRR HDQKMLTITRS----MKTEDARANNK---RARSELRISK IAMTVTCLFIISWSPY
MEL_schMan  FLCPVFIIIFSYYQIVKTVRL NELELMKMAQSLD--LQNPSAMKTGG---DKKADIEAAK TSIILVLLYLMSWSPY
MEL_homSap  FFLPLLIIIYCYIFIFRAIRE TGRALQTFGAC----KGNGESLWQRQ---RLQSECKMAK IMLLVILLFVLSWAPY
MEL_rheMac  FFLPLLIIIYCYIFIFRAIRE TGRALQTFGAC----KGSGESLWQRQ---RLQSECKMAK IMLLVILLFVLSWAPY
MEL_bosTau  FFLPLLIIIYCYIFIFKAIRE TGQALQTFGTC----EGGSECPRQRQ---RLQNEWKMAK IELLVILLFVLSWAPY
MEL_proCap  FFLPLLVIIYCYVFIFKAIRE TGRALQTFGAC----EGASETPRQWQ---RLQSEWKMAK IALLAILLYVLSWAPY
MEL_galGal  FFIPLIAIIYSYVFIFEAIKK ANKSVQTFGCK----HGNRELQKQYH---RMKNEWKLAK IALIVILLYVISWSPY
MEL_monDom  FFIPLIVIIYCYIFIFRAIQD TNKAVHSIGSG-----ESTASPRHCQ---RMKNEWKMAK IALVVILLYVLSWAPY
MEL_xenTro  FFIPLFIIIYCYIFIFKAIKN TNRAVQKIGTD-----NNKESHKQYQ---KMKNEWKMAK IALIVILLYVVSWSPY
MEL_danRer  FFIPLIVIIYCYFFIFRSIRT TNEAVGKINGD-----NKRDSMKRFQ---RLKNEWKMAK IALIVILMYVISWSPY
MEL_gasAcu  FFLPLFIIIYCYFFIFRAIRV TNRAVGKMNGSIHSHGSGRDSTKNFH---RLQNEWKMAK IALIVILLYVVSWSPY
MEL_braFlo  YFIPMGVIIYCYYNIFATVKS GDKQFGKAVKEMAHE-DVKNKAQQER---QRKNEIKTAK IAFIVITLFLSAWTPY
MEL_strPur  FVVPVTIIIVCFTRIAITVRA HRHELNKMRTKLTEDKDKKHKSSIRR-ANKAKTEFQIAK VGFQVTIFYVLSWMPY
MEL_dapPul  FFLPVSVLTFCYAAIFRFILR SSKEITRLIMTSDGTTSFSKSTVSFR-KRRRQTDVRTAL IILSLAILCFTAWTPY
BLU_dapPul  WVCPLTIITFCYAAIVRAVYR VRQNVTRV---PSQPIDNKHLHQCIN---QPNVEIAIPK IVAGLVLSWIIAWTPY
MEL2_schMa  FLCPLFLSLFCYARIILIVRS RGKDFIEM---AASSKGTNQKEKSAN-VSSSKSDTFVSK SSAILLGVYLICWTPY
MEL3_schMa  FMFPVLLCIYCYVNLLKIVRN NERVVLIS---LSNDGASKQRESVRN---RKRLDIEATK SVILSLLFYLMSWTPY
MEL_aplCal  FVLPFALMVFSYFRIWVAVRK VKSGNVFCAIRHNYNLALGSTLFVKQHRYRLHCEQKTVK IIMFLLIAFTVSWSPY
MEL2_lotGi  FVLPLCFILFAYSRILHLISS HSR--EMKSYRSAVIISKGKASIPKRFR----SERKTAI TLLITVVVFCLSWVPY
MEL_helRob  FGMPVSVIILSYIGIIRSIAK NRKEFSSLTAENSS---------------RARQEIKIAK VFAVCMTAFILCWVPY
MEL_acrMil  YFVPLAIIVYCYVFMIRSVRF MTKNAQKIW--------GVRSAAALE---TVQATWKMAK IGLIMVVGFFVAWTPY
RH7_droMel  YCIPLTSIVYSYFYILKVVFT ASRIQS-----NKD---------------KAKTEQKLAF IVAAIIGLWFLAWSPY
RH7_droYak  YCIPLTSIVYSYFYILKVVFT ASRIQS-----NKD---------------KAKTEQKLAF IVAAIIGLWFLAWSPY
RH7_droPse  YCVPLTTIVYSYFYILKVVFT ASRIQS-----NKD---------------KAKTEQKLAF IVAAIIGLWFLAWSPY
RH7_droGri  YCIPLTCIVYSYFYILKVVFT ANRIQS-----SKD---------------KAKTEQKLTF IVAAIIGLWFIAWSPY
UVV_ixoSca  WCVPLVFVTTCYSGILVTVIR SRKALA-----QES---------------R-RSELRVAK VSLALVLLWTVAWTPY
RH1_droMel  YYIPLFLICYSYWFIIAAVSA HEKAMREQAKKMN--VKSLRSSEDAE---KSA-EGKLAK VALVTITLWFMAWTPY
RH2_droMel  YYTPLFLICYSYWFIIAAVAA HEKAMREQAKKMN--VKSLRSSEDCD---KSA-EGKLAK VALTTISLWFMAWTPY
LWS1_apiMe  YYTPLFTIIYSYYFIVSAVAA HEKAMKEQAKKMN--VTSLRSGDNQN---TSA-EAKLAK VALTTISLWFMAWTPY
LWS2_apiMe  YFVPLFLIIYSYWFIIQAVAA HEKNMREQAKKMN--VASLRSSENQN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_bomTer  YFFPLFLIIWSYWFIXQAVAA HEKNMREQAKKMN--VASLRSSENQN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_catBom  YFLPLFLIIYSYFFIIQAVAA HEKNMREQAKKMN--VASLRSAENQS---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_papXut  YYTPLLLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSEAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_manSex  YFLPLLLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSEAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_vanCar  YFSPLFLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSDAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_helSar  YYAPLFLIIYSYFFIVQAVAA HEKAMREQAKKMN--VASLRSSDAAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_pieRap  YFLPLFLIVYSYWFIVQAVAA HERAMREQAKKMN--VASLRSSEQAN---TSA-ECKLAK VALMTISLWFMAWTPY
LWS_triCas  YFVPLFTIIYSYWFIVQAVAA HEKSMREQAKKMN--VASLRSSEAAQ---TSA-ECKLAK IALMTITLWFFAWTPY
LWS_rhoPro  YFLPLFTIIYSYFFILQAVSA HEKQMREQAKKMN--VASLRSAEAAN---TSA-EAKLAK VALMTISLWFMAWTPY
LWS_schGre  YLLPLGTIIYSYFFILQAVSA HEKQMREQRKKMN--VASLRSAEASQ---TSA-ECKLAK VALMTISLWFFGWTPY
LWS_meoOer  YIGPLALIIYCYFHIVSAVAT HEKQMRDQAKKMG--VKSLRTEEAKK---TSA-ECRLAK VALTTVSLWFMAWTPY
LWS_neoOer  YIGPLALIIYCYFHIVSAVAT HEKQMRDQAKKMG--VKSLRTEEAKK---TSA-GCRLAK VALTTVSLWFMAWTPY
LWS_camLud  YFLPLAITIYCYVFIIKAVAA HEKGMRDQAKKMG--IKSLRNEEAQK---TSA-ECRLAK IAMTTVALWFIAWTPY
LWS_proMil  YFLPLTITIYCYVFIIKAVAA HEKGMRDQAKKMG--IKSLRNEEAQK---TSA-ECRLAK IAMTTVALWFIAWTPY
LWS_eupSub  YLFPFFIIVYCYTYIVSAVFA HEKGMRDQAKKMG--VKSLRNEEAQK---TSA-ECRLAK VALVTVSLWFIAWTPY
LWS_homGam  YFLPLVIIVYCYTYIVAAVSA HERQMREQAKKMG--VKSLRSEESKK---TSN-ECRLAK VALTTVSLWFIAWTPY
LWS_arcGre  YYTPLLYIIYAYTFIVQAVSA HEKGMREQAKKMG--VKSLRNEEAQK---TSA-ECRLAK VALMTVSLWFMAWTPY
LWS_holCos  YLFPLAYIIYSYTFIVKAVAA HEKGMREQAKKMG--VKSLRSEEAQK---TSA-ECRLCK VALMTVTLWFMAWTPY
LWS_neoAme  YIFPLFLNIYLYTFIIKAVAN HEKQMREQAKKMG--VKSLRSEESQK---TSA-ECRLAK VALMTVSLWFMAWTPY
LWS_mysDil  YFIPLGITIYCYSYIVHAVAN HEKSMKEQAKKMG--VKSFRNEETQR---TSA-EFRLAK IALMTVSLWFIAWTPY
LWS_pedHum  YFLPLFIIIYSYIFIIQAVID HENNMRMQAKKME--VASLRSQDDKK---KSV-EIKLAK IALMTIALWFFAWTPY
RH6_droMel  YLTPLLTIIFSYWHIMKAVAA HEKAMREQAKKMN--VASLRNSEADK---SKAIEIKLAK VALTTISLWFFAWTPY
MWS_limPol  YALPLMVIIYCYIFIVKAVCD HERHLREQAKKMN--VASLRSNVDTQ---KASAEMRIAK VALVNVLLWVVSWTPY
BCR_limPol  YALPLMVIIYCYIFIVKAVCD HERHLREQAKKMN--VASLRSNVDTQ---KASAEMRIAK VALVNVLLWVVSWTPY
BCR_dapPul  YCVPLIIIIFCYYHIVRAIVH HEDALRDQAKKMN--VSSLRSNADQK---SQSAEIRVAK IAMMNITLWVAAWTPY
LWS_limPol  YFLPLITMIYCYFFIVHAVAE HEKQLREQAKKMN--VASLRANADQQ---KQSAECRLAK VAMMTVGLWFMAWTPY
LWS2_plePa  YFIPLFTLIYNYTFIVRAVSI HEDNLREQAKKMN--VTSLRANADQQ---KQSAECRLAK IALMTVGLWFIAWTPY
LWS2_hasAd  YFTPLFTLIYNYTFIVRSVSI HENNLREQAKKMN--VSSLRANADQQ---KQSAECRLAK IALMTVGLWFIAWTPY
LWS_ixoSca  YWTPLFINIYCYSKIVRAVAQ HEKQLRLQARKMN--VASLRANAEQT---KTSAEARLAK IALMTVGLWFMAWTPY
LWS1_plePa  YFVPLFIIIYCYTYIVMQVAA HEKSLREQAKKMN--IKSLRSNEDNK---KASAEFRLAK VALMTICLWFMAWTPY
LWS1_hasAd  YFVPLFIIIYCYAFIVMQVAA HEKSLREQAKKMN--IKSLRSNEDNK---KASAEFRLAK VAFMTICCWFMAWTPY
MWS_hemSan  FFLPASVIVFSYVFIVKAIFA HEAAMRAQAKKMN--VTNLRSNEAET---QRA-EIRIAK TALVNVSLWFICWTPY
RH3_droMel  FVCPTTMITYYYSQIVGHVFS HEKALRDQAKKMN--VESLRSNVDKN---KETAEIRIAK AAITICFLFFCSWTPY
RH4_droMel  FVCPTLMILYYYSQIVGHVFS HEKALREQAKKMN--VESLRSNVDKS---KETAEIRIAK AAITICFLFFVSWTPY
UVV_camAbd  YCVPMLLIIYYYSQIVGHVVS HEKALREQAKKMN--VESLRSNVNTN---AQSAEIRIAK AAITICFLFVLSWTPY
UVV_catBom  YCIPMSLIIYYYSQIVSHVVN HEKALREQAKKMN--VESLRSNTNTN---AQSAEIRIAK AAITICFLFVLSWTPY
UVV_apiMel  YCIPMILIIYYYSQIVSHVVN HEKALREQAKKMN--VDSLRSNANTS---SQSAEIRIAK AAITICFLYVLSWTPY
UVV_rhoPro  YVIPMSLIIYFYSQIVSHVII HEHNLREQAKKMN--VESLRSNANMH---TQSAEIRIAK AAITICFLFVASWTPY
UVV_manSex  YVFPMSLIIYFYSGIVKQVFA HEAALREQAKKMN--VESLRANQGGS---SESAEIRIAK AALTVCFLFVASWTPY
UVV_papXut  YIFPMIAILYFYSGIVKQVFA HEAALREQAKKMN--VDSLRSNQNAA---AESAEIRIAK AALTVCFLYVASWTPY
UVV_pedHum  YVLPLSLIIYFYTKIVLHVIN HEKSLKAQAKKMN--VESLRSDGNKN----YAVEIRITK VAIAMCFLFVISWTPY
UVV_dapPul  YVIPLAMLIFYYSKIVRSVGD HEKTLRDQAKKMN--VTSLRSNRDQN---EKSAEVRIAK VAIALATLFVFAWTPY
BLU_manSex  YCIPMALICYFYSQLFGAVRL HERMLQEQAKKMN--VKSLASNKEDN---SRSVEIRIAK VAFTIFFLFICAWTPY
BLU_apiMel  YVIPLIFIILFYSRLLSSIRN HEKMLREQAKKMN--VKSLVSN-QDK---ERSAEVRIAK VAFTIFFLFLLAWTPY
RH5_droMel  YVIPMTMILVSYYKLFTHVRV HEKMLAEQAKKMN--VKSLSANANAD---NMSVELRIAK AALIIYMLFILAWTPY
UVV_plePay  WFIPVAAIVFFYVQIFLAVKD HEEKIKEQARKMN--VDSIRSNEAVK---NSSAEVRIAK TAMCVFLMFLSSWAPY
UVV_hasAda  WFIPVAAIIFFYAQIFLAVKD HEEKIKEQARKMN--VDSFRSNEALK---NSSAEVRIAK TAMCVVLLFLTSWVPY
MEL_plaDum  FIFPVAIIFFCYLGIVRAIFA HHAEMMATAKRMG--A-N--TGKADA---DKKSEIQIAK VAAMTIGTFMLSWTPY
MEL_lotGig  FVVPLGVIIFCYVFIIKSVMN HEKEMAKMADKLD--AKD--VRSTKE---KAKAEIKIAK VSMTIILLYLMSWTPY
MEL_sepOff  FCFPILIIFFCYFNIVMAVSN HEKEMAAMAKRLN--AKE--LRKAQA---GASAEMKLAK ISIVIVTQFLLSWSPY
MEL_todPac  FFGPILIIFFCYFNIVMSVSN HEKEMAAMAKRLN--AKE--LRKAQA---GANAEMRLAK ISIVIVSQFLLSWSPY
MEL_entDof  FMLPIIIIAFCYFNIVMSVSN HEKEMAAMAKRLN--AKE--LRKAQA---GASAEMKLAK ISMVIITQFMLSWSPY
MEL_schMed  FIIPVGIIIFCYYQIVKAVRV HELEMLKMAQKMN--ASHPTSMKTGA----KKADVQAAK ISVIIVFLYMLSWTPY
MEL_schMan  FLCPVFIIIFSYYQIVKTVRL NELELMKMAQSLD--LQNPSAMKTGG---DKKADIEAAK TSIILVLLYLMSWSPY
MEL_patYes  FLIPLIIIGVCYVLIIRGVRR HDQKMLTITRS----MKTEDARANNK---RARSELRISK IAMTVTCLFIISWSPY
MEL_homSap  FFLPLLIIIYCYIFIFRAIRE TGRALQTFGAC----KGNGESLWQRQ---RLQSECKMAK IMLLVILLFVLSWAPY
MEL_rheMac  FFLPLLIIIYCYIFIFRAIRE TGRALQTFGAC----KGSGESLWQRQ---RLQSECKMAK IMLLVILLFVLSWAPY
MEL_bosTau  FFLPLLIIIYCYIFIFKAIRE TGQALQTFGTC----EGGSECPRQRQ---RLQNEWKMAK IELLVILLFVLSWAPY
MEL_proCap  FFLPLLVIIYCYVFIFKAIRE TGRALQTFGAC----EGASETPRQWQ---RLQSEWKMAK IALLAILLYVLSWAPY
MEL_galGal  FFIPLIAIIYSYVFIFEAIKK ANKSVQTFGCK----HGNRELQKQYH---RMKNEWKLAK IALIVILLYVISWSPY
MEL_monDom  FFIPLIVIIYCYIFIFRAIQD TNKAVHSIGSG-----ESTASPRHCQ---RMKNEWKMAK IALVVILLYVLSWAPY
MEL_xenTro  FFIPLFIIIYCYIFIFKAIKN TNRAVQKIGTD-----NNKESHKQYQ---KMKNEWKMAK IALIVILLYVVSWSPY
MEL_danRer  FFIPLIVIIYCYFFIFRSIRT TNEAVGKINGD-----NKRDSMKRFQ---RLKNEWKMAK IALIVILMYVISWSPY
MEL_gasAcu  FFLPLFIIIYCYFFIFRAIRV TNRAVGKMNGSIHSHGSGRDSTKNFH---RLQNEWKMAK IALIVILLYVVSWSPY
MEL_braFlo  YFIPMGVIIYCYYNIFATVKS GDKQFGKAVKEMAHE-DVKNKAQQER---QRKNEIKTAK IAFIVITLFLSAWTPY
MEL_strPur  FVVPVTIIIVCFTRIAITVRA HRHELNKMRTKLTEDKDKKHKSSIRR-ANKAKTEFQIAK VGFQVTIFYVLSWMPY
MEL_dapPul  FFLPVSVLTFCYAAIFRFILR SSKEITRLIMTSDGTTSFSKSTVSFR-KRRRQTDVRTAL IILSLAILCFTAWTPY
BLU_dapPul  WVCPLTIITFCYAAIVRAVYR VRQNVTRV---PSQPIDNKHLHQCIN---QPNVEIAIPK IVAGLVLSWIIAWTPY
MEL2_schMa  FLCPLFLSLFCYARIILIVRS RGKDFIEM---AASSKGTNQKEKSAN-VSSSKSDTFVSK SSAILLGVYLICWTPY
MEL3_schMa  FMFPVLLCIYCYVNLLKIVRN NERVVLIS---LSNDGASKQRESVRN---RKRLDIEATK SVILSLLFYLMSWTPY
MEL_aplCal  FVLPFALMVFSYFRIWVAVRK VKSGNVFCAIRHNYNLALGSTLFVKQHRYRLHCEQKTVK IIMFLLIAFTVSWSPY
MEL2_lotGi  FVLPLCFILFAYSRILHLISS HSR--EMKSYRSAVIISKGKASIPKRFR----SERKTAI TLLITVVVFCLSWVPY
MEL_helRob  FGMPVSVIILSYIGIIRSIAK NRKEFSSLTAENSS---------------RARQEIKIAK VFAVCMTAFILCWVPY
RH7_droMel  YCIPLTSIVYSYFYILKVVFT ASRIQS-----NKD---------------KAKTEQKLAF IVAAIIGLWFLAWSPY
RH7_droYak  YCIPLTSIVYSYFYILKVVFT ASRIQS-----NKD---------------KAKTEQKLAF IVAAIIGLWFLAWSPY
RH7_droPse  YCVPLTTIVYSYFYILKVVFT ASRIQS-----NKD---------------KAKTEQKLAF IVAAIIGLWFLAWSPY
RH7_droGri  YCIPLTCIVYSYFYILKVVFT ANRIQS-----SKD---------------KAKTEQKLTF IVAAIIGLWFIAWSPY
UVV_ixoSca  WCVPLVFVTTCYSGILVTVIR SRKALA-----QES---------------R-RSELRVAK VSLALVLLWTVAWTPY
MEL_acrMil  YFVPLAIIVYCYVFMIRSVRF MTKNAQKIW--------GVRSAAALE---TVQATWKMAK IGLIMVVGFFVAWTPY

(continued shortly)

The carboxy-terminal tail and VxPx motif

This distinctive region has quite baffling length variation across -- and sometimes within -- opsin classes. The extent of conservation also differs greatly, with no real universally conserved residues past the end of the seventh transmembrane helix. The observed terminal conservation pattern for a given opsin must be indicative of its functional importance, even as that stands today insufficiently explained by arrestin phosphoserine or cysteine palmityolation sites, opsin dimerization or other membrane macro organization, or interaction with Galpha proteins. Some interactions would seem to require commonality across all orthology classes (or larger assemblages such as ciliary opsins) while others do not.

Several studies have implicated the carboxy terminal motif VxPx of ciliary opsins as the intra-cellular targeting motif for proteins that function within cilia (or modified apical cilia such as rod and cone outer segments). The phylogenetic origin or age of this motif function has not been established nor its lineage-specific variations, though cilia themselves are pre-metazoan and the need to direct opsins specifically to outer segments would have been present already prior to lamprey divergence.

The description of the recognition pattern as VxPx alone is unsatisfactory: it is too short and vapid to serve this purpose. The residues valine and proline are all but inert and valine would be hard for the recognition apparatus to distinguish from leucine and isoleucine. Valine and proline would occur by random in this pattern in 4 proteins per thousand; mis-targeting would arise frequently from de novo substitutions in situations where one of V or P was already present. Thus the motif must reflect the end-of-gene position, ie VxPx* properly describes the motif and internal VxPx cannot.

In opsins, we see from cytoplasmic tail alignments below that RGR, peropsin, neuropsins, melanopsins, PPINb and TMT all lack any sign of a terminal VxPx motif. Here TMT is surprising in its total lack of any distal conservation whereas its nearest relative encephalopsin does have a strongly conserved VxPA motif VxPL, x:RK). RHO1 (VAPA), RHO2 (VSPA), SWS2 (VxPy, x:SAG, y:AS), LWS (VxPA X:AS), PPIN (VxPy x:AS, Y:ASLV), PARIE (VxPy x:AST, y:AVL), PIN VxPy x:MTA, y:AS), and VAOP (VxPy x:CY, y:ILM; motif lost in Aves).

Thus the motif is really quite constrained in second and fourth position to a non-bulky uncharged side chain; VxPx does not accurately describe the observed reduced alphabet at these positions. However the carboxy terminus might have other functionalities in addition to ciliary targeting at least in opsins. Conversely it is not so clear that PPIN, PIN, PARIE, VAOP and encephalopsin are specifically targeted to modified pineal, brain, and melanocyte cilia in the same sense that rod and cone opsins are.

Photoreceptor retinol dehydrogenase RDH8, another enzyme of the cis-retinal regeneration cycle located in the outer segments, also terminates in a similar motif VRPR. This is not the case for RDH11, RDH12 or RDH16 nor in arrestin, transducin subunits, cGMP phosphodiesterase subunits, cGMP-gated channel subunits, Na/K/Ca exchanger, RGS9, R9AP, guanylate cyclases 2D and 2F, guanylate cyclase activating protein, phosducin, and recoverin.

RGR

The first hand-gapped alignment below illustrates these issues using RGR from 53 species. The alignment begins inside the last transmembrane segment with the Schiff base lysine K and continues past the NAxxY motif at a deeply invariant length (totaling 19 residues) to the "YR" motif found in almost all GPCR. This marks the beginning of the carboxy terminal cytoplasmic tail, which in RGR is fairly fixed at 23 residues, remain alignable and may extend the transmembrane helix but bear no resemblance to any other opsin or GPCR.

The degree of conservation establishes selection is at work. It appears that RGR must terminate in several charged (characteristically basic) residues regardless of length indels. These could possibly associate electrostatically with membrane phospholipid or be important to initial establishment of topology. Mammals have in effect lost the YR motif though most have an R one residue later. This does not quite coincide with the advent of ERY or GRY mammals in cytoplasmic loop C2.

Conservation of G.WQ.L..Q has persisted for tens of billions of years and cannot be explained by helix or beta sheet per se -- possibly it is constrained by interaction with parts of the other cytoplasmic face. It appears that arrestin could recognize phosphoserine or threonine in almost all species but palmityolation cannot be widespread. A few species, such as guinea pig, microbat and armadillo may be exhibiting early stages of pseudogenization or at least partial loss of function.

Absent any experimental information or relevant 3D structure or capacity for annotation transfer from homologous regions, the specifics of individual residue and residue patch conservation will remain difficult to explain. 

             K..PT.NA..YaLG.E.yr .G.Wq.L..q..........k.K    
>RGR_homSap  KMVPTINAINYALGNEMVC RGIWQCLSPQKRE-----KDRTK   RGR_homSap  KMVPTINAINYALGNEMVC RGIWQCLSPQKREKDRTK      
>RGR_panTro  KMVPTINAINYALGNEMVC RGIWQCLSPQKSE-----KDRTK   RGR_panTro  ................... ...........S......      
>RGR_gorGor  KMVPTINAINYALGNEMVC RGIWQCLSPQKSK-----KDRTK   RGR_ponPyg  ................... ...........S......      
>RGR_ponPyg  KMVPTINAINYALGNEMVC RGIWQCLSPQKSE-----KDRTK   RGR_gorGor  ................... ...........SK.....      
>RGR_nomLeu  KMVPTINAVNYALGNEMVC RGIWQCLSPQKSE-----KDRAK   RGR_nomLeu  ........V.......... ...........S....A.      
>RGR_macMul  KMVPTINAINYALGNEMVC RGIWQCLSPQKSE-----KDRAK   RGR_macMul  ................... ...........S....A.      
>RGR_papHam  KMVPTINAINYALGNEMVC RGIWQCLSPQKSE-----KDRAK   RGR_papHam  ................... ...........S....A.      
>RGR_calJac  KMVPTIDAINYALGNEMIC RGIWQCLSPQKSE-----KDRTK   RGR_calJac  ......D..........I. ...........S......      
>RGR_tarSyr  KTVPTINAYHYALGSEMVC RGIWQCLSPHSSE-----.....   RGR_tarSyr  .T......YH....S.... .........HSS.           
>RGR_otoGar  KTVPTINAVNYALGSEMVC RGIWQCLSLQRSK-----QDGAK   RGR_otoGar  .T......V.....S.... ........L.RSKQ.GA.      
>RGR_micMur  KTVPTINAINYALGSETVC RGIWQCLSPQRSE-----QDRAK   RGR_micMur  .T............S.T.. ..........RS.Q..A.      
>RGR_tupBel  KMVPTVNAVNYALGSETIC RGIWGCLSP-KRE-----RDRAR   RGR_tupBel  .....V..V.....S.TI. ....G....KR-.R..AR      
>RGR_musMus  KTMPTINAINYALHREMVC RGTWQCLSPQKSK-----KDRTQ   RGR_musMus  .TM..........HR.... ..T........SK....Q      
>RGR_ratNor  KTMPTINAINYALRSEMVC RGTWQCRSAQKSK-----QDRTQ   RGR_ratNor  .TM..........RS.... ..T...R.A..SKQ...Q      
>RGR_cavPor  KTVPTINAINYSLG----- RGPWQSLEMQRSK-----QD      RGR_cavPor  .T.........S..R---- -.P..S.EM.RSKQ.         
>RGR_dipOrd  KMVPTVNAINYALCNELLC GGFSLGLLPQKGK-----QDRTQ   RGR_dipOrd  .....V.......C..LL. G.FSLG.L...GKQ...Q      
>RGR_oryCun  KTVPTVNAVNYALGSEVIR RGIWQCLLPQRSV-----RGRAQ   RGR_oryCun  .T...V..V.....S.VIR .......L..RSVRG.AQ      
>RGR_ochPri  KAVPTVNAINYALGSEVIR RGIWQCLLPQRSV-----RDRAQ   RGR_ochPri  .A...V........S.VIR .......L..RSVR..AQ      
>RGR_bosTau  KAVPTVNAMNYALGSEMVH RGIWQCLSPQRRE-----HSREQ   RGR_bosTau  .A...V..M.....S...H ..........R..HS.EQ      
>RGR_susScr  KMVPTVNAINYALGGEMVH RGIWQCLSPQRRE-----RDREQ   RGR_susScr  .....V........G...H ..........R..R..EQ      
>RGR_canFam  KAAPTINAIHYALGGDMVH GGLWQCLSPQRSQ-----PDRAR   RGR_canFam  .AA......H....GD..H G.L.......RSQP..AR      
>RGR_felCat  kaVPTINAINYALGSEMVH RGIWQCLSPQGSG-----LDRAR   RGR_felCat  .A............S...H ..........GSGL..AR      
>RGR_equCab  KTVPTINAVNYALGSEMLH RGIWQCLSPQKSE-----RDRAQ   RGR_equCab  .T......V.....S..LH ...........S.R..AQ      
>RGR_myoLuc  KMVPTVNAVNYALGS---- -GIWQRLSLQ.............   RGR_myoLuc  .....V..V.....S---- -....R..L.              
>RGR_pteVam  KMAPTINAVNYALGSEMVQ RGIWQCLSPQRSE-----RDHAQ   RGR_pteVam  ..A.....V.....S...Q ..........RS.R.HAQ      
>RGR_sorAra  KTVPTVNALHYGLGSGMVQ NGFRKGLWLQRRE-----RERAL   RGR_sorAra  .T...V..LH.G..SG..Q N.FRKG.WL.R..RE.AL      
>RGR_eriEur  ktVPTVNAVHYVLGSEKVH KGFWQCFSPQRSE-----QDRAR   RGR_eriEur  .T...V..VH.V..S.K.H K.F...F...RS.Q..AR      
>RGR_loxAfr  KAVPVINACHYALGSEVVR GGIWQYLSRQRGESPLRARDRTH   RGR_loxAfr  .A..V...CH....S.V.R G....Y..R.RG.SPLRAR DRTH
>RGR_proCap  KAVPIVNACHYALGSETVH RGIWQCLSRQRGESPPRTRDRTQ   RGR_proCap  .A..IV..CH....S.T.H ........R.RG.SPPRTR DRTQ
>RGR_echTel  KAVPIVNACHYALGSETVH RGIWQCLSRQRGESPPRTRDRTQ   RGR_echTel  .A..IV..CH....S.T.H ........R.RG.SPPRTR DRTQ
>RGR_choHof  KTMPTINAFQYALGSETVC RDIWQCLPRLRSMGRSSGHD      RGR_choHof  .TM.....FQ....S.T.. .D.....PRLRSMGRSSGH D   
>RGR_dasNov  KTMPTVNALYYALGRESVH RNA                       RGR_dasNov  .TM..V..LY....R.S.H .NA                      
>RGR_ornAna  KTVPVIDAFTYALRNEDYR GGIWQFLTGQKIERV-EVENKIK   RGR_ornAna  .T..V.D.FT...R..DYR G....F.TG..I.RVEVEN KIK
>RGR_xenTro  KTSPAVNAYVYGLGNENYR GGIWQYLTGQKLEKA-ETDNKTK   RGR_xenTro  .TS.AV..YV.G....NYR G....Y.TG..L..AE.DN KTK
>RGR_xenLae  KISPAVNAYVYGLGNENYR GGIWLYLTGQKLEKA-ETDSRTK   RGR_xenLae  .IS.AV..YV.G....NYR G...LY.TG..L..AE.DS RTK
>RGR1_danRer KTSPTFNVFVYALGNENYR GGIWQLLTGQKIESP-AIENKSK   RGR1_danRe  .TS..F.VFV......NYR G....L.TG..I.SPAIEN KSK
>RGR1_takRub KTCPTINVFLYALGNENYR GGIWQFLTGEKIEAP-QIENKSK   RGR1_gasAc  .TS..F.VFL......NYR G....L.TGE.IDVPQIEN KSK
>RGR1_tetNig KTCPTVNVFLYALGNENYR GGIWQFLTGEKIETP-QLENKTK   RGR1_gadMo  .TA..F.VFL......NYR G....L.TGE.I.VPQIEN KSK
>RGR1_gasAcu KTSPTFNVFLYALGNENYR GGIWQLLTGEKIDVP-QIENKSK   RGR1_takRu  .TC....VFL......NYR G....F.TGE.I.APQIEN KSK
>RGR1_oryLat KTSPTFNPLLYALGNENYR GGIWQFLTGEKIHVP-QDDNKSK   RGR1_tetNi  .TC..V.VFL......NYR G....F.TGE.I.TPQLEN KTK
>RGR1_gadMor KTAPTFNVFLYALGNENYR GGIWQLLTGEKIEVP-QIENKSK   RGR1_oryLa  .TS..F.PLL......NYR G....F.TGE.IHVPQDDN KSK
>RGR2_danRer KTSPIFHAVLYAYGNEFYR GGVWQFLTGQK-----SAD-KKK   RGR2_danRe  .TS.IFH.VL..Y...FYR G.V..F.TG..SADKKK
>RGR2_pimPro KTSPIFHAAMYAYGNEFYR GGIWQFLTGQK-----PAD-KKK   RGR2_pimPr  .TS.IFH.AM..Y...FYR G....F.TG..PADKKK
>RGR2_tetNig KTNPIFNALLYTFGNEFYR GGVWHFLTGHKIVDP-VLK-KSK   RGR2_tetNi  .TN.IF..LL.TF...FYR G.V.HF.TGH.IVDPVL.K SK
>RGR2_gasAcu kTNPIFNALLYSFGNEFYR GGVWHFLTGQKMVDP-VVK-KSK   RGR2_gasAc  .TN.IF..LL.SF...FYR G.V.HF.TG..MVDPVV.K SK
>RGR2_oryLat KTNPFFNALLYSFGNEFYR GGVWNFLTGQKIVEP-DVK-KSKQK RGR2_hipHi  .TN.IF..LL.SF...FYR G.V.HF.TG..IVDPVV.K SK
>RGR2_oncMyk KTNPISNAWLYSFGNEFYR GGVWQFLTGQKFTEP-VVV-KLKGR RGR2_oryLa  .TN.FF..LL.SF...FYR G.V.NF.TG..IVEPDV.K SKQK
>RGR2_espLuc KMNPIFNALLYSFGNEFYR GGVWQFLTGQKFTEL-VVV-KLKGR RGR2_poeRe  .TN.IF..FL.SF...FYR G.V.NF.TG..IVEPDV.K SK
>RGR2_gadMor KTNPISNALLYSFGNESYR SGVWHFLTGQKFVEP-SFK-KIK   RGR2_oncMy  .TN.IS..WL.SF...FYR G.V..F.TG..FTEPVVVK LKGR
>RGR2_poeRet KTNPIFNAFLYSFGNEFYR GGVWNFLTGQKIVEP-DVK-KSK   RGR2_espLu  ..N.IF..LL.SF...FYR G.V..F.TG..FTELVVVK LKGR
>RGR2_hipHip KTNPIFNALLYSFGNEFYR GGVWHFLTGQKIVDP-VVK-KSK   RGR2_gadMo  .TN.IS..LL.SF...SYR S.V.HF.TG..FVEPSF.K IK

Peropsin

Peropsin exhibits greater conservation both in its post-K helix and in its cytoplasmic tail than RGR. The FR motif is perfectly conserved throughout vertebrates. Length, ancestrally 32 residues, experienced an era of variability in amniotes but then settled down to a fixed 35 residues in mammals. The difference alignment shows that a central motif EITISN conserved in early vertebrates changed character completely (to TMPVTS) in mammals, though the earlier motif still appears faded in platypus. A cysteine conserved back to invertebrates might be palmitoylated; conserved serines and threonines offer potential phosphorylation sites.

The cytoplasmic tail of peropsin is completely unalignable to RGR. Unlike RGR, tblastn of peropsin tail against whole human genome elicits matches to imaging opsins and a GPCR (neuropeptide Y receptor). While these matches are weak and largely driven by the last transmembrane section alone, 3 early tail residues (*) emerge as possible conserved residues. Whether or not homologically valid, this suggests modeling of the first 9 residues of peropsin tail by known bovine rhodopsin structure. 

                                  *  * *
peropsin   KSSTFYNPCIYVVANKKFR RAMLAMFKC
           KS+T YNP IYV  N++FR   +L +F C
LWS opsin  KSATIYNPVIYVFMNRQFR NCILQLF  
RHO opsin  KSAAIYNPVIYIMMNKQFR NCMLTTICC
NPY2R GPCR ..STFANPLLYGWMNSNYR KAFLSAFRC

Conserved   ksstfynpciyv.ankkFR rAm.aMfkCqthq.mpvts.lpm.vsq.pl.sgr.  
PER_homSap  KSSTFYNPCIYVVANKKFR RAMLAMFKCQTHQTMPVTSILPMDVSQNPLASGRI       PER_homSap  KSSTFYNPCIYVVANKKFR RAMLAMFKCQTHQTMPVTS ILPMDVSQNPLASGRI      
PER_panTro  KSSTFYNPCIYVVANKKFR RAMLAMFKCQTHQTMPVTSILPMDVSQNPLASGRI       PER_panTro  ................... ................... ................      
PER_gorGor  ksstfynpciyvvankKFR RAMLAMFKCQTHQTMPVTSILPMDVSQNPLASGRI       PER_gorGor  ................... ................... ................      
PER_ponPyg  KSSTFYNPCIYVVANKKFR RAMLAMFKCQTHQTMPVTSILPMDVSQNPLASGRI       PER_ponPyg  ................... ................... ................      
PER_nomLeu  KSSTFYNPCIYVVANKKFR KAMLAMFKWPNHQTMPGTSILPMDVSQNPLTSGKI       PER_nomLeu  ................... K.......WPN.....G.. ...........T..K.      
PER_macMul  KSSTFYNPCIYVVANKKFR RAMLAMFKCQTHQTMPVTSILPMDVSQNPLASGRI       PER_macMul  ................... ................... ................      
PER_papHam  KSSTFYNPCIYMVANKKFR RAMLAMFKCQTHQTMPVTSILPMDVSQNPLASGRI       PER_papHam  ...........M....... ................... ................      
PER_calJac  KSSTFYNPCIYVVANKKFR RAMLAMLKCQTHQTMPVTSVLPMDISQNPLASGRI       PER_calJac  ................... ......L............ V....I..........      
PER_tarSyr  ksstfynpciyvvankKFR RAMFAMLKCQTYQAMPATSSLPMNVSQNPLTSGKN       PER_tarSyr  ................... ...F..L....Y.A..A.. S...N......T..KN      
PER_otoGar  KSSTFYNPCIYVVANKKFR RAMFAMFKCQTHQAMAVTSILPMDISQNPLASRRI       PER_otoGar  ................... ...F.........A.A... .....I.......R..      
PER_micMur  KSSTFYNPCIYVIANKKFR RAMFAMFKCQTHQAMPVTSIFPMGVSQNPLPSGRT       PER_micMur  ............I...... ...F.........A..... .F..G......P...T      
PER_tupBel  KSSTFYNPCIYVLANKKFR KAMCAMFKCQTHQAMSVTSVLPMASSPRPLAPARV       PER_tupBel  ............L...... K..C.........A.S... V...AS.PR...PA.V      
PER_musMus  KSSTFYNPCIYVAAHKKFR KAMLAMFKCQPHLAVPEPSTLPMDMPQSSLAPVRI       PER_musMus  ............A.H.... K.........P.LAV.EP. T....MP.SS..PV..      
PER_ratNor  KSSTFYNPCIYVAANKKFR KAMFAMLKCQPHQAMPEPSTLAMGVPHSPLAPARI       PER_ratNor  ............A...... K..F..L...P..A..EP. T.A.G.PHS...PA..      
PER_ochPri  KSSTFYNPCIYVAANKRSR RAMFAMFKCQIPQAKPVTSLSPRDVSQSPLSSGRT       PER_cavPor  ............I...... ...F...Q.....AV..A. .....A..S.......      
PER_cavPor  KSSTFYNPCIYVIANKKFR RAMFAMFQCQTHQAVPVASILPMDASQSPLASGRI       PER_dipOrd  ................... ......L......A..... ................      
PER_speTri  KSSTFYNPCIYVAANKRFR RAMFAMFKCQTHQAMPVTSVLPMDVSQSPRASGRI       PER_speTri  ............A...R.. ...F.........A..... V.......S.R.....      
PER_oryCun  KSSTFYNPCIYVAANKRFR RAMFAMFKCQTHQAMPVTSVLPMDVSQNPLPSGII       PER_ochPri  ............A...RS. ...F......IP.AK.... LS.R....S..S...T      
PER_dipOrd  KSSTFYNPCIYVVANKKFR RAMLAMLKCQTHQAMPVTSILPMDVSQNPLASGRI       PER_oryCun  ............A...R.. ...F.........A..... V..........P..I.      
PER_bosTau  KSSTFYNPCIYVIANKKFR RAMLAMFKCQTTQAMPVTSVLPMDVPQNPLTSGKV       PER_bosTau  ............I...... ...........T.A..... V.....P....T..KV      
PER_turTru  KSSTFYNPCIYVIANKKFR RAMLAMFKCQTHQAMPMESILPMDVPQNPLTSGKV       PER_turTru  ............I...... .............A..ME. ......P....T..KV      
PER_susScr  KSSTFYNPCIYVIANKKFR RAMLAMFKCQTHQAMPLESTLPMDVPQNPLASGRV       PER_vicVic  ............I...... .............A..M.. ......P....T...L      
PER_vicVic  KSSTFYNPCIYVIANKKFR RAMLAMFKCQTHQAMPMTSILPMDVPQNPLTSGRL       PER_susScr  ............I...... .............A..LE. T.....P........V      
PER_canFam  KSSTFYNPCIYVVANKKFR KAIFAMFKCQTHQAMPGTSILPMDVSQNPLASGRN       PER_canFam  ................... K.IF.........A..G.. ...............N      
PER_felCat  ksstfynpciyvvankKFR KAMFAMFKCENRQPMPVTSILPMDVSQNPLTSGRK       PER_felCat  ................... K..F.....ENR.P..... ...........T...K      
PER_equCab  KSSTFYNPCIYVVANKKFR RAMFAMFKCQTHRAMPVTSILPMDVPQNQLASGRI       PER_equCab  ................... ...F........RA..... ......P..Q......      
PER_myoLuc  KSSTFYNPCIYVVANKKFR RAMFAMFKCQTHQTMTTMSFLPMDVPQNPLTSGRI       PER_myoLuc  ................... ...F...........TTM. F.....P....T....      
PER_pteVam  KSSTFYNPCIYVVANKKFR RAMFAMFKCQDHQSMPVTSVLPMDVPQNPLTSGRI       PER_pteVam  ................... ...F......D..S..... V.....P....T....      
PER_eriEur  KSSTFYNPCIYVLANKKFR RAMFAMFKCQTHQAMPVTNTLPMDIPQK-LDSRRN       PER_eriEur  ............L...... ...F.........A....N T....IP.K-.D.R.N      
PER_sorAra  KSSTFYNPCIYVVANKKFR RAMSAMLTCRAQGAMPAASTLPMDAAHSPQASGRN       PER_sorAra  ................... ...S..LT.RAQGA..AA. T....AAHS.Q....N 
PER_loxAfr  KSSTFYNPCIYVVANKKFR RAMFAMFKCQTHQAEPVTCILPMNVSQNPLAAGRI       PER_loxAfr  ................... ...F.........AE...C ....N.......A...      
PER_echTel  ksstfynpciyvvankKFR RAMFALLQCQPQEARRVTSILPMNVSQNPMASGRL       PER_echTel  ................... ...F.LLQ..PQEARR... ....N.....M....L      
PER_proCap  KSSTFYNPCIYVVANKKFR RAMLAMFKCQTHQAVPVTNILPMTVSQNSSASGRI       PER_proCap  ................... .............AV...N ....T....SS.....      
PER_choHof  KSSTFYNPCIYVVANKKFR TIMFAMLKCQTHQAVPVTSILPMNVSENPLASGRI       PER_choHof  ................... TI.F..L......AV.... ....N..E........      
PER_dasNov  KSSTFYNPCIYVVANKKFR RAIFAMLKCQTHQAMPVMSILPMNVSENPLASGRI       PER_dasNov  ................... ..IF..L......A...M. ....N..E........      
PER_monDom  KSSTFYNPCIYVAANKKFR RAISAMIRCQTHQSMPISNALPMN                  PER_monDom  ............A...... ..IS..IR.....S..ISN A...N       
PER_macEug  KSSTFYNPCIYVAANKKFR RAISAMMRCETHQSMPVSNALPLNLT                PER_macEug  ............A...... ..IS..MR.E...S...SN A..LNLT     
PER_ornAna  KSSTFYNPCIYVVANKKFR RAMLSMVQCQTHREITITDVLPMNRSRSPLTL          PER_ornAna  ................... ....S.VQ....REITI.D V...NR.RS..TL    
PER_galGal  KSSTFYNPCIYVIANKKFR RAILAMVRCQTRQEITISNALPMTVSLSALTS          PER_galGal  ............I...... ..I...VR...R.EITISN A...T..LSA.T.    
PER_taeGut  KSSTFYNPCIYVIANKKFR RAILAMVRCQTRQEITINNALPMSVSQSALTSQNSSHLPA  PER_taeGut  ............I...... ..I...VR...R.EITINN A...S...SA.T.QNSSHL PA
PER_anoCar  KSSTFYNPCIYVIANKRFR RAILAMIRCQTRQEITINNVLPMSVSQSTIA           PER_anoCar  ............I...R.. ..I...IR...R.EITINN V...S...STI.     
PER_xenTro  KSSTFYNPCIYVIANKKFR RAILSMVQCKSRQEVTLDNHFPMNVSQSTLTT          PER_xenTro  ............I...... ..I.S.VQ.KSR.EVTLDN HF..N...ST.TT    
PER_danRer  KSSTFYNPCIYVIANKKFR RAIIGMIRCQTRQRVTINNQLPMMASSVPLNP          PER_danRer  ............I...... ..IIG.IR...R.RVTINN Q...MA.SV..NP    
PER_gasAcu  KSSTFYNPCIYVIANKKFR RAIIGMVRCQTRQRITINSQVPMTTSQQPLTQ          PER_gasAcu  ............I...... ..IIG.VR...R.RITIN. QV..TT..Q..TQ    
PER_oryLat  KSSTFYNPCIYVIANKKFR RAIIGMIRCQTRQRITISTQVPMTISQQPLTQ          PER_oryLat  ............I...... ..IIG.IR...R.RITIST QV..TI..Q..TQ    
PER_takRub  KSSTFYNPCIYVIANKKFR RAIIGMIRCQTRQQMTINTEIPMTTSQQTATQ          PER_takRub  ............I...... ..IIG.IR...R.Q.TINT EI..TT..QTATQ    
PER_tetNig  KSSTFYNPCIYVITNKKFR QAIIGMIRCQTRQQITINTDIPMTASQQTLTQ          PER_tetNig  ............IT..... Q.IIG.IR...R.QITINT DI..TA..QT.TQ    
PER_calMil  KSSTFYNPCIYVIANKKFR KAIMAMICCQNRQEITINHTLPMTISRVPLTE          PER_calMil  ............I...... K.IM..IC..NR.EITINH T...TI.RV..TE    
PER1b_sacK  KIPAVFNPVIYVALNPEFR KYFGKTIGCRRKRKKPIAVRLNGSEQNVENTI          PER1b_sacK  .IPAVF..V...AL.PE.. KYFGKTIG.RRKRKK.IAV R.NGSEQNVENTI

Neuropsins

Here NEUR1 is a bit unusual in the last transmembrane helix terminating in FA instead of the FR found in the other neuropsin classes. It is not clear how a neutral alanine affects signaling at this key residue. Conceivably the helix is longer and a more distal conserved FR plays this role 19 aminio acids later. The length and sequence of the carboyx terminus is strongly conserved out to the stop codon in available species implying functional significance.

However this region is completely unalignable to other neuropsins past the FR motif. In other neuropsins the carboxy terminus is poorly conserved and alignable past the FR motif only by 6, 10, and 24 residues in NEUR2-4. Some termini are quite extended in seemingly random sequence. 

NEUR1_homS KSAAMYNPIIYQVIDYKFA CCQTGGLKAT-KKKSLEGFR LHTVTTVRKSSAVLEIHEEV
NEUR1_nomL KSAAMYNPIIYQVIDYKFA CCQTGGLKAT-KKKSLEGFR LHTVTSVRKSSAVLEIHEEV
NEUR1_panT KSAAMYNPIIYQVIDYKFA CCQTGGLKET-KKKSLEGFR LHTVTTVRKSSAVLEIHEEV
NEUR1_ponP KSAAMYNPIIYQVIDYKFA CCQTGGLKAT-KKKSLEGFR LHTVTTVRKSSAVLEIHEEV
NEUR1_macM KSAAMYNPIIYQVIDYKFA CCQTGGLKAT-KKKSLEGFR LHTVTTVRKSSAVLEIHEEV
NEUR1_papH KSAAMYNPIIYQVIDYKFA CCQTGGLKAT-KKKSLEGFR LHTVTTVRKSSAVLEIHEEV
NEUR1_calJ KSAAMYNPIIYQVIDYKFA CCQTGGLKAT-KKKSLEDFR LHTVTTVRKSSAVLEIHEEV
NEUR1_tarS KSAAMYNPIIYQVIDYKFA CCQTGGLKAT-KKKSLEDFR LHTVTTVRKSSAVLEIHEEV
NEUR1_equC KSAAMYNPIIYQVIDYKFA CCQTGGLKAT-KKKSLEDFR LHTVTTVRKSSAVLEIHQEV
NEUR1_oryC KSAAMYNPIIYQVIDYKFS CCRTSGLKAT-KKKSLEDFR LHTVTTVRKSSAVLEIHQEV
NEUR1_canF KSAAMYNPIIYQVIDYKFA CCQTGRLKAT-KKKSLEDFR LNTVTTVRKSSAVLEIHQEV
NEUR1_sorA KSAAMYNPIIYQVIDYRFA CCQSGGLRAT-KKKSLDDFR LHTVTTVRESSAVLEIHQEV
NEUR1_bosT KSAAMYNPIIYQVIDYKFA CCQTGGLKAT-KKKSLEDFR LHTVTTVRKSSAVLEVHQEV
NEUR1_susS KSAAMYNPIIYQVIDYKFA CCQTGGLKAT-KKKSLEDFR LHTVTTVRKSSAVLEIRQEV
NEUR1_pteV KSAAMYNPIIYQVIDYKFA CCQTSGLRAT-KKKSLEDFR LHTITTVREASAVLEIHQEV
NEUR1_musM KSAAMYNPIIYQVIDYRFA CCQAGGLRGT-KKKSLEDFR LHTVTTVRKSSAVLEIHQEV
NEUR1_ratN KSAAMYNPIIYQVIDYRFA CCQTGGLRAT-KKKSLEDFR LHTVTAVRKSSAVLEIHPEV
NEUR1_cavP KSAAMYNPIIYQVIDSRFA CCQNAGLKAT-KKKSLEDFR LHTVTTDRKS-AVLEIHQEV
NEUR1_ochP KSAAMYNPIIYQVIDYKFS CCRTGGLKQT-KKKSLEDFR LHTVTTVRKSSAVLEIHQEV
NEUR1_speT KSAAMYNPIIYQVIDYKFA CCQTGGLKAT-KKKSLEDFR LHTVTAVRKSSAVVEIHQEV
NEUR1_myoL KSSAMYNPIIYQVIDYKLA CCQTGGLRAT-KKKSLENFR LHTVTTVRKSSAVLEIHQEV
NEUR1_felC KSAAMYNPIIYQVIDYKFA CCQTGGLKAT-KKKSLEDFR LHTVTTVRKSSAVLEIHQEV
NEUR1_eriE KSAAMYNPIIYQVIDYKFA CCQTGGLKAN-KKKSLKDYR LHTVTTVRRSSAVLEIHQEV
NEUR1_otoG KSAAMYNPIIYQVIDYKFA CCQTGGLKTT-KKKSLEDFR LHTVTTVRKSSAVLEIHQEV
NEUR1_turT KSAAVYNPIIYQVIDYKFA CCQTGGLKAT-KKKSLEDFR LHTVTTVRKSSAVLEIHQEV
NEUR1_vicV KSAAMYNPIIYQVIDYKFA CCQTGGLKAT-KKKSLEDFR LHAVTTVRKSSAVLEIHQEV
NEUR1_loxA KSAAMYNPIIYQVIDYKFA CCQTGGLRAT-KKKSLEGFR LHTVTTVKKSSAVLEVHQEV
NEUR1_dasN KSAAMYNPIIYQVIDYKFA CCQTGGLRAT-KKKSLEDFR LHTVTTVRESSAVLEVHQEV
NEUR1_proC KSAAMYNPIIYQVIDYKFA CCRTRGLRAT-KEKSLEGVR LHTVTTVRKSSAVLEIHQEV
NEUR1_choH KSAAMYNPIIYQVIDYKFA CCRTGGLRAT-KKKSFEGFR LHTVTTVRKSSAVLEIHQEV
NEUR1_monD KSAAMYNPIIYQVIDCKFA CCQSGGQKAA-KKESLRTYR SHSMSTIRKPSAVSGPHQEV
NEUR1_ornA KSAAMYNPIIYQVIDCRIS CCRLGGPKTG-KKESLKNSR LHTVTTVRKSSAVLEIHEEV
NEUR1_galG KSAAMYNPIIYQVIDCKFA CCRSGGPKTLQKKSSLKESR MYTISSHRDSAALSGTQLEV
NEUR1_taeG KSAAMYNPIIYQVIECRLA CCRPGG---LKAKSSLKKSR TYTISAHRDSTAMNETQLEA
NEUR1_anoC KSAAMYNPVIYQVIDCKSA CCRPGNLQPLQKK----NSR ...
NEUR1_xenT KSASMYNPIIYQVIDCKPA CCKKDKS--LQNT----TSR VYTISTFRKSTTSAR
NEUR1_danR KSSAMYNPIIYQVIDCKKK CVKSCCFQAWRKKKPSKTSR FYTISGSIKQRPGDEASIEI
NEUR1_takR KSSAMYNPIIYQVVDVKTS CTNFSCCKALKERIHFRKSR FYSISASMKKRPANEVPTEI
NEUR1_tetN KSSAMYNPIIYQVADLKTS CTSSSCCKALKERVLFRKSR YTISGSLRDTLPPKEAHIEM
NEUR1_gasA KSSAMYNPIIYQVLDLKNS CMKSSCFKGLKKPRHFRKSR YTISGSLRDTLPPKEAHIEM
NEUR1_oryL KSSAMYNPIIYQVLDLKNS CMKSSCFKGLKKPRH---FR YTISGSLKDTAPAKEAHIEI
NEUR1_pimP KSSAMYNPIIYQVIDCKKN CAKLSCFQAWSKRKHYKTSR FYSISASMKKRPANEVPTEI
NEUR1_petM KSAAMYNPLIYQLLSRRGT GAHCCRCRKARGTLRR--PR ...

NEUR2_galG KSSTLYNPIIHLLLKPNFR SNIAKD FTVIQQLCVRCCFCVKELQTYRSTFNTGLRTFKGK--NESSCNALPIMEGCSYFP...
NEUR2_anoC KSSTLYNPAMYLFLKPNFR STIAKD LTVLHRLCLKSCFCPRGMQNCSYRSALEAPLKSFKGRNESSSNSVQIVGGCSYFP... 
NEUR2_xenT KSSTIYNPVVYLLLKPNFL NVVTKD LTLFQTMCAVVCGWCRTPAVKTPCPHKDLKTTSKPPSSFKKSQGVHRICLSHSKASP...
NEUR2_oncM KSSTIYNPIIYLLLRPNFR RVMYRD LVSLCRAFLKGCLCSCSQGAVGKCHSHLVVRVSLQSFCRLPGHGQSCSPTSSARQALGESRG 
NEUR2_danR KSSTIYNPMVYLLFKPNFR KSLSQD TQMFRHRICLSHSKASPSPGMKDQERQSSQQCNNKDGSISTPFSSGQAESYGA
NEUR2_pimP KSSTIYNPMVYLLFKPNFR KILSQD TQNIRHRMCVSHSKASPTPEIKAQSSQQCKDATISTPFSSGQAESYGT 
NEUR2_tetN KSSTIYNPLVYLLCKPNFR ECLYKD TSTLRQRIYRGSPLSGPRDRSGGV-TQRHKDLSVSTRLSNGQQDSYGT 
NEUR2_takR KSSTIYNPVVYLLCKPNFR ECLYKD TSTLRQRIYRGSPQSEPRERFGGT-SQRHKDLSISTRLSNGQQDSYGT 
NEUR2_gasA KSSTIYNPVVYLLCKPNFR ACLYRD TTLLRQRIYRGSPRSEPKAHFGST-SQRNKDMSVSVRSSNGQQDSYGA 
NEUR2_oryL KSSTIYNPMVYLLCKPNFR ECLCRD TSLLRHMIYRGSPQPQER--FGSD-SRRNKDITASTRFSNGQQESYGA 
 
NEUR3_galG KSSTAYNPFIYYIFSKTFR HEIKQLQCCW GWRVHFFSADNSAENSVSMMWSGRDNIRLSPTAKVESQGAARH 
NEUR3_taeG KSSTAYNPFIYYVFSKTFR CEVKRLQCCC AWRVHYFSSDNSVENPLSTMWSGRDNIRLSAAPQVQNPGAAAP 
NEUR3_xenT KSSTAFNPMIYYAFSKTFR RKVKHLKCCC GWRVHFLQSENSVENPRVSVIWTGKENVMVSSVPKLMKGVPGTPTGTQ 
NEUR3_anoC KSSTAYNPFIYYTFSKTFR HEVKHLRCYS GQRAQENMKNSINSNVSFMWHGGGNICLSTRQIEMREIPNQ 
NEUR3a_dan KCSTVYNPLVYYVFRKSFR REIHQIRICC FQGCWDAVSKMTRGDGPEETSGTHETDNI 
NEUR3a_tet KSSTVYNPVIYYIFSQSFK LEVQQLFLCC LSFRSSRTNNCKSNESSIFMVSNGKNLTPALTQQNTSHAVIMN 
NEUR3a_tak KSSTAYNPFIYFFFQRNTG HKLLPFHRHAFSCSDRADSSREGEKEESKVSKNLGFTCFGAGTYETCPGLAGDQSQREMAELG 
NEUR3a_gas KSSTVYNPFIYFIFQRSSW RELLRLHRHLLCCWHRASPPAEGRRSQRGSEGGSWGGACESDDAFGLVHVMKSNATCQTISWA 
NEUR3b_dan KTSTVYNPFIYYIFSKTFK REVNQLSRFC GRSNICRPTDAKNRPENTIYLVCDVNKSKPGVEDLSLARSKENETQMLPNQDLHE 
NEUR3b_ory KSSTVYNPMIYYFFSKSFQ REVKQLSWLC VGSNPCHVSNSVNDNNIYMVSVNVKSKETRRETLQEITESRQEDITNERVER 
NEUR3b_tet KSSTVYNPVIYYIFSQSFK LEVQQLFLCC LSFRSSRTNNCKSNESSIFMVSNGKNLTPALTQQNTSHAVIMN 
NEUR3b_tak KSSTVYNPIIYYMFSQSFK MEVQQLFLWC PSFEFCRTSSNNGNETTIYMVSTGKT 
NEUR3b_gas KSSTVYNPLIYYIFSQSFR REVKQLWRHL GSTLCSVSNSVNDAAVSNTGKSN 

NEUR4_ornA KSASFYNPIIYFGMNSKFR KDILVLLPCAKESKEPVKLKKFKNLR QKQGFTLQKPEKAHVLQV 
NEUR4_galG KSASFYNPIIYFGMSSKFR RDIFILFHCAKEVKDPVKLKRFKNLK QKQEPSQKEEKYAAEMHPA 
NEUR4_taeG KSASFYNPIIYFGMSSKFR RDIFIFHCAKELKDPVKLKRFKNLKP KQPQPSQKEEKYAPEMHPA 
NEUR4_anoc KSASFYNPIIYFGMSSKFR KDIFVLLHCAKEIKDPVKLKRFKNLK QKQEVSPSQREEKYAADVQPA 
NEUR4_xenT KSASFYNPLIYFGMSSKFR KDLCVVLPCAKAQKDPVKLKRYKDKK QGSAPRAREQTEIEQPVQLQPA 
NEUR4_danR KSASFYNPLIYFGLSSKFR KDVSVLLPCGREGRDPVRLKRFKRLR GRAEPPGAPAHTPHPQIALKNYNNHSKPHAGPAHCTGH 
NEUR4_tetN KSASFYNPLIYFGMSSKFR KDVSLILPCAKERREVVLLQRFKNIK PKAAAAPPPPPLPVYRPKEKNEDEPKLSV 
NEUR4_gasA KSASFYNPLIYFGMSSKFR KDVSVLVPCTRERREVVHLQHFKNIK PKAEAPPTPASLPVQKLGAKYAVPN 
NEUR4_calM KSASFYNPMIYFGLNSKFR KDIYILLPCVKEPKESVKLKRFKHLR HRPEQQQANKDRYAEELQQV 
NEUR4_petM KSASFYNPFIYFGMSGKFR ADVRAMLPCRATSVKAPRDAVRLKRY RTHVDPERASHRAAVAAREQPAPRAAAPRPASPAP

Melanopsins

The cytoplasmic tail in melanopsin can be quite variable in length and sequence. No strongly conserved residues exist in bilateran melanopsins beyond the P.L beginning at position 8; consequently very little can be learned about the cytoplasmic tail of vertebrate or even arthropod melanopsins from study of molluscan melanopsins. Its contribution to structure and function of the cytoplasmic face must be quite variable. Note the FR motif is almost always YR outside of lophotrochozoans.

Within just vertebrates, the cytoplasmic tail of melanopsin exhibits much more extensive conservation of 11 residues extending out to position 66 (human numbering). The two conserved serines might be cyclically phosphorylated and the single cysteine at position 9 palmitoylated (as it cannot be in a disulfide residing in the reduced cytoplasmic milieu). While the remaining residues are very likely stably structured, it's not clear whether they interact primarily with the other cytoplasmic loops or with auxiliary proteins. The latter is more likely recalling that melanopsins signal via Gq and the inositol triphosphate cascade rather than the very different cyclic nucleotide pathway.

MelCytoTail.jpg


just vertebrates: full length cytoplasmic tail, mammals
MEL1_homSa KASAIHNPIIYAITHPKYR VAIAQHLPCLGVLLGVSRRHSRPYPSYRSTHRSTLTSHTSNLSWISIRRRQESLGSESEVGWTHMEAAAVWGAAQQANGRSLYGQGLEDLEAKAPPRPQGHEAETPGKTKGLIPSQDPRM
MEL1_panTr KASAIHNPIIYAITHPKYR VAIAQHLPCLGVLLGVSRRHSRPYPSYRSTHRSTLISHTSNLSWISIRRRQESLGSESEVGWTHMEAAAVWGAAQQANGRSLYGQGLEDLEAKAPPRPQGHEAETPGKTKGLIPSQDPRM
MEL1_ponpy KASAIHNPIIYAITHPKYR VAIAQHLPCLGVLLGVSRRHSRPYPSYRSTHRSTMISHTSNLSWISGRRRQESLGSESEVGWTHMEAAAVWGAAQQANGRFLYDQGLEDLEAKAPPRPQGEEAETPGKTKGLIPSQDPRM
MEL1_rheMa KASAIHNPIIYAITHPKYR VAIAQHLPCLGVLLGVSRRHSHPYPSYRSTHRSTLISHTSNLSWISGRRRQESLGSESEVGWTHMEAAAVWGAAQQANGRSLYGQGLEDLEAKAPPRPQGQEAETPGKTKGLLPCKDSRM
MEL1_calJa KASAIHNPIIYAITHPKYR VAIAQHLPCLGVLLGVSRRHSHPYPSYRSTHRSTLISHTSNLSWISGRRRQESLGSESEVGWTHMEAAAAWGAAQQANGRSLYGHGLEDLEAKAPPRPQRQEAETPGKTKGLIPSQDPRM
MEL1_otoGa KASAIHNPIIYAITHPKYR VAIAQHLPCLGLLLGVSRQHSRPYPSYRFTHHSTLSSQASDLSWISGRRRQESLGSESEVGWTDMEAAATWGAALQVSGQCPYSQGLEDMEAKGPLRPQGPETKTSGKTKGLLPSLDPRM
MEL1_musMu KASAIHNPIIYAITHPKYR VAIAQHLPCLGVLLGVSGQRSHPSLSYRSTHRSTLSSQSSDLSWISGRKRQESLGSESEVGWTDTETTAAWGAAQQASGQSFCSQNLEDGELKASSSPQVQRSKTPKTKGHLPSLDLGM
MEL1_ratNo KASAIHNPIIYAITHPKYR AAIAQHLPCLGVLLGVSGQRSHPSLSYRSTHRSTLSSQSSDLSWISGQKRQESLGSESEVGWTDTETTAAWGAAQQASGQSFCSHDLEDGEVKAPSSPQEQKSKTPKTKRHLPSLDRRM
MEL1_nanSp KASAIHNPIIYAITHPKYR LAISQHLPCLGVLIGVSSQRSHPSLSYRSTHRSTLSSQASDLSWISGRKRQESLGSESEVGWTDTEVTAAWGVAQEASGWSPYRHSLEDGEVKASPSPQGQEAKTSRKTKGQLPSLNLRM
MEL1_phoSu KASAIHNPIVYAITHPKYR AAIAQHLPCLGVLLGVSSQRNRPSLSYRSTHRSTLSSQSSDLSWISAPKRQESLGSESEVGWTDTEATAVWGAAQPASGQSSCGQNLEDGMVKAPSSPQAKGQLPSLDLGM
MEL1_bosTa KASAIYNPIIYAITHPKYR LAIAQHLPCLGVLLGVSGQRTGLYTSYRSTHRSTLSSQASDLSWISGRRRQASLGSESEVGWMDTEATAAWGAGQQVSGWSPCSQRLDDVEAKALPRPQGRDSEAPGKAKGLLPNLDARM
MEL1_canfa KASAIHNPIIYAITHPKYR MAIAQHLPCLGVLLGVSGQRTGPYASYRSTHRSTLSSQASDLSWISGRRRQASLGSESEVGWMDTEAAAVWGAAQPAGGRFLCTQGLEDAEAKAPLRPRGQAVETPGKTKGRLPSLDPSR
MEL1_felCa KASAIHNPIIYAITHPKYR MAIAQHLPCLGVLLGVSGQHTGPYASYRSTHRSTLSSQASDLSWISGRRRQASLGSESEVGWMDTEAAAVWGAAQQVSGRFPCSQGLEDREAKAPVRPQGREAETPGQTKGLLPSQDPRM
MEL1_equCa KASAIHNPIIYAIIHPKYR MAIAQHLPCLGVLLGVSSQRTRPYTSYRSTHRSTLSSQGSDLSWISGRRRQASLGSESEVGWMDTEAAAVWGAAQQMSGWSPCGQGLEDMEAKAPPRPQGWEGEALRKIKGLLPSLDPRM
MEL1_micMa KASAIHNPIIYAITHPKYR VAIAQHLPCVGVLLGVSRQHSRPYPSYRSTHRSTLSSQASDLSWISGRRRQESLGSE
MEL1_eriEu KASAIHNPIIYAITHPKYR MAIAQHLPCLRVLLGVSGQRDRPYTSYRSTHRSTLSSQISDLSWVSRRRRQASLGSESEVGWTDTEVAAVWGTMSGHFPCGQGLDDMEAKAAHNPRGLEAETPGKIKGLLPSLDPQM
MEL1_loxAf KASAIHNPIIYAITHPKYR MAIAQHLPCLGVMLGVSGQRTRPYTSYHSTLHSTLSSQASDLSWISGRRRQASLGSESEVGWTDTEAAAAWEGAQQVSGQASCSQALQNLEANTPPRPQGWGPETPRK
MEL1_proCa KASAIHNPIIYAITHPKYR MAIAQHLPCLGVLLGVSDQHTRPYTSYRSTHHSTLSSQASDISWISGRRRQASLGSESEVGWTDTEAAAAWEGAQQVSGRASCSQVLESMEANTPPRPQGWGPETPRK
MEL1_dasNo KASAIHNPIVYAITHPEYR MAIAQHLPCLGLLLGVLGHRPRPGSSPGSTRCSAHSGQASGLSWISRQRRRASLGSKDEVGWEDVEAAAASGAAGQESGRSPRAQDLEHMEAEAARWPSWEAEPEK
MEL1_monDo KASAIHNPIIYAISHPKYR MAIAQNFPCLRALLCVRHPRTRSFSSYRFTRRSTMTSQASDISWLPRGRRQLSLGSESEIGWNNMEAGTTSLTSRNQQGSCRMDQETMETRELAAIAKAKGRSWETLEKTLEEMDDSSLLE
MEL1_smiCr KASAIHNPIIYAISHPKYR MAIAQNFPCLRAVLGIRHPRTQSFSSYRFTHRSTTASQASDISWQSRGRRQLSLGSESEAGWNNIETGLTLRSLEGSCGMDEETMDTRELSASTKAKGQSWETLAKTLEEMDDLSLLE
MEL1_ornAn KSSAIHNPIIYAITHPKYR MAITKYIPCLGPLLRVSRQDSRSSSHYASSRRSTVTSQSLDGSWLPGRRRPLSSASDSESGWTDTAADAGSASSRAASRQVSYRMSQGPTEHCDLRAKVKPKSWEVGSFQK
MEL1_taeGu KASVIHNPIIYAITHPKYR KAIATYVPCLGPLLRVSPKDSRSFSSYHSSRRATISSQSSEISGLQERKRRLSSLSDSESGCTETETDTPSMFSRLARRQISYKTDKDTTQTSDIRAKLTSQDSGWGVA
MEL1_galGa KASAIHNPIIYAITHPKYR TAIATYVPCLGFLLRVSPKESRSFSSYPSSRRTTITSQSSETSGLQKGKRRLSSISDSESGCTDTETDITSMISRPASSQVSYEMGEDTTQTSDLGGKPKVKSHDSGIFGKAVVDADEIPM
MEL1_xenTr KASAIHNPIIYAITHPKYR MAIAKYIPCLGSLLRVKRRDSRSYSSYPSSRRSTVTSHCSQSSDVGGHPKLKNHLPSVSDSESGWTDTEADSSVNSRPASRQVSYEMGKDTTETNDLKSKAKLKSHDSGIFEKTSMDADDISL
MEL1_anoCa KASVIHNPIIYAIVHPKYR MAIAKFLPCLGSLLRVPRKDSSYPSTRRPTVTSQSSDINGVPRGHRRLSSVSDSESDWTDTEADISSQNSRVASGSISYRIYEDTTETIKVKSKMRSHDSGIFERTSVDADDISM
MEL1a_danR KASAIHNPIIYAITHPKYR LAIAKYIPCLRLLLCVPKRDLHSFHSSLMSTRRSTVTSQSSDMSGRFRRTSTGKSRLSSASDSESGWTDTEADLSSMSSRPASRQVSCDISKDTAEMPDFKPCNSSSFKSKLKSHDSGIFEKSSSDVDDVSV
MEL1_takRu KASAIHNPIIYAITHPKYR LALAKYIPCLGFLLCISPHELQSTSSSFMSLRRSTVTSQTSDISGQFRPQSKPRRSSASDSESCLTDTEADLSSMGSRPASRQVSCDISRDTTELPEYKPASSFNSKVKSPDSGIFEKTSFDFDASM
MEL1_gasAc KASAIHNPIIYAITHPKYR IALAKYIPFLGVLLCVPPRELRSASSSFRSTRRSTVTSQTSDVSSQQRRQGSRNSRLSSASDSESCLTDTEADGSSVGSRPASRQVSCDIGRDTAELPEFKPSSSFKSKMKSHDSGIFEKSYDTDISM
MEL1_oryLa KASAIHNPIIYAITHPKYR MALAKYIPGLGVLLCIHPKDLRSASSSFVSTRRSTVTSQSSDISSQLRRQSTFKSRLSSLSDSESGLTDTEADLSSLSSRPASRQVSCEISRDTAELPDFKHTSSFKAKLKNNDSGIFEKTSFDTVSI
MEL1b_danR KASAIHNPIIYAITHPKYR SAIAKYIPCLGVLLCVPRRDRFSSSSFISTRRSTLTSQSSETSSNLHRAGKARLSSVSDSESGWTDTEADLSTASSRPASRQVSSEIRKDLCDIKHSSSLRLKVKSRDSGIFDRQNDVS
MEL1_rutRu KASAIHNPIIYAITHPKYR AAIARYIPVLRTILRVKEKELRSSFSSGSVSSRRPTLSSQCSLGVSIGNNGRWGKKRLSSASDSDSCWTESEADGSSVSSLTFGRRVSTEISTDTVILSPGSSNSTASGQKSEKAHKVVSVPVPSITFETDSA
MEL1_astBu KASAIHNPIIYAITHPKYR AAIGHYVPFLRSVLRLQEKDLRSSFSSSATSSRCTTFTSSPKGRLNANGHQAQNRLSSVSDSKSCWMESDADGSSRRSERQAFSEATANPLDSTTPRQHVGHTDASSSDGAVLEAKLPL
MEL2_galGa KASAIYNPIIYAIIHPRYR KTIHNAVPCLRFLIRISKNDLLRGSINESSFRTSLSSHQSLAGRTKNTCVSSVSTGEANWSDVELDTVEPAHEKLQPRRSHSFSSSLRQKRDLLPDSYSCSEETEEKVSLSSSY
MEL2_taeGu KASAIYNPIIYAIIHPRYR KTIHQAVPCLRFLIRISKNDLLRGSINESSFRTSLCSHHSLAGKTKSICVSSISTGEATWSNVELDPVEPAQEKLKPRRSNSFSTSLRQEKRDLLPKTCSYDAATAQKVSLSSSC
MEL2_anoCa KASAIYNPIIYAIIHPRYR RTIRSAVPCLRFLIPISKSDLSTSSMSESSFRASVSSRHSFSYRNKSTYISSISAKETTWCDVELDPVESGHKKLQAYRSNSFSAKGVAEEESGLLLRTNNCNVPARKKVALSSIS
MEL2_podSi KASAIYNPIIYAIIHPRYR RTIRSAVPCLRFLIRISPSDLSTSSVNESSFRASMSSRHSFAARNKSSCVSSISAAETTWSDMELEPVEAARKKQQPHRSRSFSKQAEEETGLLLKTQSCNVLTGEKVAVSSIS
MEL2_tetNi KASAIYNPIIYAIIHPRYR KTIRSAVPCLRFLIPISKSDLSTSSMSDSSFRSALSCRHSYRSRSTYISSISAKETTWCDVELDPVESGHKKLQAYRSNSFSAKGVAEEESGLLLRTNNCNVPARKK
MEL2_gadMo KASAIYNPFIYAIIHSKYR DTLAEHVPCLYFLRQPPRKVSMSRAQSECSFRDSMVSRQSSASKTKFHRVSSTSTADTQVWSDVELDPMNHEGQSLRTSHSLGVLGRSKEHRGPPAQQNRQTRSSDTLEQATVADWRPPL
MEL2_xenLa KASAIYNPIIYGIIHPKYR ETIHKTVPCLRFLIREPKKDIFESSVRGSIYGRQSASRKKNSFISTVSTAETVSSHIWDNTPNGHWDRKSLSQTMSNLCSPLLQDPNSSHTLEQTLTWPDDPSPKEILL
MEL1a_calM KASAIHNPIIYAITHPKYR MAIAKYVPLLGLLLRVSRRDSRTSGQYYSTRRSTLTSQTSDLSGYPRGKGRLSSASDSES
MEL2_danRe KSSAIYNPFIYAIIHNKYR RTLAEKVPGLSCLSRSQKDGLSSSTNSDASAQDSSVSRQSSVSKNRLHSTMVQ
MEL2_gasAc KASAIYNPFIYAIIHNKYR MTLAAKFPCLRFLSPTPRKDTSSSISESSYRDSVISRQSTASRTHFITACPDTVN

all eumetazoan
taxon  consensus  KASA..NPI.YAI.HPKYR  .......P.L.........
loph  MEL1_todPa  KASAIHNPMIYSVSHPKFR  EAISQTFPWVLTCCQFDDK
loph  MEL1_plaDu  KASARYNPIIYALSHPKFR  AEIDKHFPWLLCCCKPKPK
loph  MEL1_lotGi  KASAMHNPVIYALSHPKFR  DAVSKLMPWFLCCCGLTDA
loph  MEL1_sepOf  KASAIHNPLIYSVSHPKFR  EAIAENFPWIITCCQFDEK
loph  MEL1_entDo  KASAIHNPIVYSVSHPKFR  EAIQTTFPWLLTCCQFDEK
loph  MEL1_patYe  KSSSMHNPVVYALSHPKFR  KALYQRVPWLFCCCKPKEK
loph  MEL1_capCa  KASAMWNPILYALSHPKFR  AALEDHMPWLLVC
loph  MEL_schMed  KTSAMYNPFIYAINHPKFR  IQLEKKFPCLICCCPPKPK
loph  MEL1_schMa  KTSAVYNPIVYAVKHPKFR  MEIEKRFPFLICCCPPKPK
loph  MEL3_schMa  KMAAIYNPILYAFTNRKFK  NALGIRKTSSVIMQQQRLL
loph  MEL_aplCal  KTSMVFNPILYSISHPKVR  KRIANLACCYSVRRHQQQT
loph  MEL2_lotGi  KLSTVTNPILYSLSHPVVR  NKLFLRLRHELYRRPSDSV
arth  CHEL_LWS_l  KANSCYNPIVYGISHPRYK  AALYQRFPSLAC-GSGESG
arth  CHEL_LWS_i  KANACYNPIVYGISHPKYR  AALARRFPSLVCMPPGGDQ
arth  INSE_LWS1_  KANAIYNPIVYGISHPKYR  AALKEKLPFLVCGSTEDQT
arth  INSE_LWS2_  KANAVYNPIVYGISHPKYR  AALFAKFPSLACAAEPSSD
arth  CRUS_LWS_m  KANAVYNPIVYAISHPKYR  AALYKKLPCLACSTESADE
arth  CRUS_LWS_n  KSNAVYNPIVYAISHPKYR  AALYKKLPCLACSTESADE
arth  INSE_LWS_d  KANAVCNPIVYGLSHPKYK  QVLREKMPCLACGKDDLTS
arth  INSE_MWS1_  KSAACYNPIVYGISHPKYR  LALKEKCPCCVFGKVDDGK
arth  INSE_MWS_c  KSAACYNPIVYGISHPKYG  IALKEKCPCCVFGKVDDGK
arth  INSE_MWS2_  KTSAVYNPIVYGISHPKYR  IVLKEKCPMCVFGNTDEPK
arth  INSE_UVV_c  KFVACLDPYVYAISHPRYR  LELQKRLPWLE--LQEKPV
arth  INSE_BLU_m  KVVSCIDPWVYAINHPRYR  AELQKRLPWMGVREQDPDA
arth  INSE_BLU_a  KTVSCIDPWIYAINHPRYR  QELQKRCKWMGIHE--PET
arth  INSE_BLU_d  KSVSCLDPWVYATSHPKYR  LELERRLPWLGIREKHATS
arth  INSE_UVV_r  KAVACVDPYVYAISHPRYR  KAFQRFFFKNVITPSQTGG
arth  INSE_UVV2_  KTASCIDPFVYAATNRRFR  NELKRKYRKRSRYQPSLKT
cnid  ENC_nemVec  KTSACYNPIIYFFMYSKFR  QELSKKFPWLDIKEAPAPS
mamm  MEL1_homSa  KASAIHNPIIYAITHPKYR  VAIAQHLPCLGVLLGVSRR
mamm  MEL1_rheMa  KASAIHNPIIYAITHPKYR  VAIAQHLPCLGVLLGVSRR
mamm  MEL1_calJa  KASAIHNPIIYAITHPKYR  VAIAQHLPCLGVLLGVSRR
mamm  MEL1_otoGa  KASAIHNPIIYAITHPKYR  VAIAQHLPCLGLLLGVSRQ
mamm  MEL1_micMu  KASAIHNPIIYAITHPKYR  VAIAQHLPCVGVLLGVSRQ
mamm  MEL1_bosTa  KASAIYNPIIYAITHPKYR  LAIAQHLPCLGVLLGVSGQ
mamm  MEL1_susSc  KASAIYNPIIYAITHPKYR  MAIAQHLPCLGVLLGVSGQ
mamm  MEL1_equCa  KASAIHNPIIYAIIHPKYR  MAIAQHLPCLGVLLGVSSQ
mamm  MEL1_myoLu  KASAIHNPIIYAITHPKYR  MAIAQHLPCLGLLLGVSGQ
mamm  MEL1_pteVa  KASAIHNPIIYAITHPKYR  MAIAQHLPCLGVLLGMSGQ
mamm  MEL1_felCa  KASAIHNPIIYAITHPKYR  MAIAQHLPCLGVLLGVSGQ
mamm  MEL1_canFa  KASAIHNPIIYAITHPKYR  MAIAQHLPCLGVLLGVSGQ
mamm  MEL1_proCa  KASAIHNPIIYAITHPKYR  MAIAQHLPCLGVLLGVSDQ
mamm  MEL1_eriEu  KASAIHNPIIYAITHPKYR  MAIAQHLPCLRVLLGVSGQ
mamm  MEL1_musMu  KASAIHNPIIYAITHPKYR  VAIAQHLPCLGVLLGVSGQ
mamm  MEL1_ratNo  KASAIHNPIIYAITHPKYR  AAIAQHLPCLGVLLGVSGQ
mamm  MEL1_nanEh  KASAIHNPIIYAITHPKYR  LAISQHLPCLGVLIGVSSQ
mamm  MEL1_phoSu  KASAIHNPIVYAITHPKYR  AAIAQHLPCLGVLLGVSSQ
mamm  MEL1_smiCr  KASAIHNPIIYAISHPKYR  MAIAQNFPCLRAVLGIRHP
mamm  MEL1_monDo  KASAIHNPIIYAISHPKYR  MAIAQNFPCLRALLCVRHP
mamm  MEL1_loxAf  KASAIHNPIIYAITHPKYR  MAIAQHLPCLGVMLGVSGQ
mamm  MEL1_ornAn  KSSAIHNPIIYAITHPKYR  MAITKYIPCLGPLLRVSRQ
tetr  MEL1_anoCa  KASVIHNPIIYAIVHPKYR  MAIAKFLPCLGSLLRVPRK
tetr  MEL1_taeGu  KASVIHNPIIYAITHPKYR  KAIATYVPCLGPLLRVSPK
tetr  MEL1_galGa  KASAIHNPIIYAITHPKYR  TAIATYVPCLGFLLRVSPK
tetr  MEL1_xenTr  KASAIHNPIIYAITHPKYR  MAIAKYIPCLGSLLRVKRR
tetr  MEL1_danRe  KASAIHNPIIYAITHPKYR  LAIAKYIPCLRLLLCVPKR
tetr  MEL1_takRu  KASAIHNPIIYAITHPKYR  LALAKYIPCLGFLLCISPH
tetr  MEL1_gasAc  KASAIHNPIIYAITHPKYR  IALAKYIPFLGVLLCVPPR
tetr  MEL1_oryLa  KASAIHNPIIYAITHPKYR  MALAKYIPGLGVLLCIHPK
vert  MEL1_calMi  KASAIHNPIIYAITHPKYR  MAIAKYVPLLGLLLRVSRR
vert  MEL1_petMa  KASAIHNPIVYAITHPKYR  
deut  MEL1a_braF  KSSAVYNPIVYAITHPKFR  AAVKKHIPCLSGCLPADEE
deut  MEL1a_braB  KSSAVYSPIVYAITYPKFR  EAVKKHIPCLSGCLPASEE
deut  MEL1_strPu  KCSAIWNPIIYCLSHEKFN  AALKEK---LMGMCGIEIP
deut  MEL1b_braB  KLTVIINPIVYVLSIPNFR  KALFAQEREKYASEDVVLT
tetr  MEL2_galGa  KASAIYNPIIYAIIHPRYR  KTIHNAVPCLRFLIRISKN
tetr  MEL2_taeGu  KASAIYNPIIYAIIHPRYR  KTIHQAVPCLRFLIRISKN
tetr  MEL2_anoCa  KASAIYNPIIYAIIHPRYR  RTIRSAVPCLRFLIPISKS
tetr  MEL2_podSi  KASAIYNPIIYAIIHPRYR  RTIRSAVPCLRFLIRISPS
tetr  MEL2_xenLa  KASAIYNPIIYGIIHPKYR  ETIHKTVPCLRFLIREPKK
fish  MEL2_gadMo  KASAIYNPFIYAIIHSKYR  DTLAEHVPCLYFLRQPPRK
fish  MEL2_tetNi  KASAIYNPIIYAIIHPRYR  KTIRSAVPCLRFLIPISKS
fish  MEL2_danRe  KSSAIYNPFIYAIIHNKYR  RTLAEKVPGLSCLSRSQKD
fish  MEL2_gasAc  KASAIYNPFIYAIIHNKYR  MTLAAKFPCLRFLSPTPRK

Encephalopsin

This opsin class, despite its phylogenetically erratic pattern of tetrapod gene loss, is exceedingly conserved in its carboxy terminus in both length and sequence back to lamprey. This conservation is unprecedented in this region and must reflect mission-critical binding to another protein.

The cytoplasmic tail of encephalopsin has no detectable homology to other ciliary opsins for more that 6 residues beyond the FR motif (FRRSLLQL) even though it shares the same very ancient terminal exon break as other ciliary opsins (phase 0, just prior to the FR). The VxPx* motif can be recognized in the conserved pattern VRPL*; if this primarily drives cell targeting to cilia, it may or may not have arisen independently from similar motifs in other ciliary opsins.

An interesting phyloSNP can be seen in the difference alignment in the primate stem (S-->N) two residues after the critical Schiff lysine. This may slightly shift the chemical environment of the chromophore. 

ENCEPH_hom KSNTVYNPVIYVFMIRKFR RSLLQLLCLRLLRCQRPAKDLPA-AGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDDSDKT-NGSKVDVIQVRPL   
ENCEPH_pan KSNTVYNPVIYVFMIRKFR RSLLQLLCLRLLRCQRPAKDLPA-AGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDDSDKT-NGSKVDVIQVRPL   
ENCEPH_mac KSNTVYNPVIYVFMIRKFR RSLLQLLCLRLLRCQRPAKDLPA-AGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDDSDKT-NGSKVDVIQVRPL   
ENCEPH_pap KSNTVYNPVIYVFMIRKFR RSLLQLLCLRLLRCQRPAKDLPA-AGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDDSDKT-NGSKVDVIQVRPL   
ENCEPH_pon KSNTVYNPVIYVFMIRKFR RSLLQLLCLRLLRCQRPAKDLPA-AGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDDSDKT-NGSKVDVIQVRPL   
ENCEPH_nom KSNTVYNPVIYVLMIRKFR RSLLQLLCLRLLRCQRPAKDLPA-AGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDDSDKT-NGSKVDVIQVRPL   
ENCEPH_cal KSNTVYNPVIYVFMIRKFR RSLLQLLCLRMLRCQQPAKDLSA-AGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDDSDKT-NGSKVDVIQVRPL   
ENCEPH_tar KSNTVYNPVIYIFMIRKFR RSLLQFLCLRLLRCQQPAKDLPA-AENEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDDSDKT-SGSKVDVIQVRPL   
ENCEPH_mic KSNTVYNPIIYIFMIRKFR RSLLQLLCFRLLRCQRPAKDLPA-SESEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDNSDKT-SGSKVDVIQVRPL   
ENCEPH_oto KSNTVYNPVIYIFMLRKFR RSLLQLLCFRLLRCQRPAKDLPA-AESEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDNSDKT-NGSKVDVIQVRPL   
ENCEPH_tup KSSTVYNPVIYIFMIRKFR RSLLQLLCFRLLRYQRPAKDLPA-AGSEMQIRPIVMSQKDGD---KPKKKVTFNSSSIIFIITSDESLSVDDSDKT-SGSKVDVIQVRPL   
ENCEPH_dip KSSTIYNPVIYIFMIRKFR RSLLQLLCFRLLRCQRPAKDLPA-AGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDDSVRS-SGSKADVIQVRPL   
ENCEPH_ory KSSTAYNPIIYIFMIRKFR RSLLQLLCFQPLRCQQPPKDLPT-VGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIIASDESLAVDDNEKA-SGPKVDVIQVRPL   
ENCEPH_mus KSSTVYNPVIYIFMNRKFR RSLLQLLCFRLLRCQRPAKNLPA-AESEMHIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVEDSDRS-SASKVDVIQVRPL   
ENCEPH_rat KSSTVYNPVIYIFMIRKFR RSLLQLLCFRLLRCQRPAKNLPA-AESEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVEDSDRS-SASKVDVIQVRPL   
ENCEPH_cav KSSTVYNPVIYVLMIRKFR RSLLQLHCLRLLRCQQPAKDLPA-VEREMHIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDDSDRT-SGSKVDTIQVRPL   
ENCEPH_spe KSSTVYNPVIYIFMIRKFR RSLLQLLCSRLLRCQQPAKDLPA-VGNEMQIRPIVISQKDGE---RPKKKVTFNSSSIVFIITSDESLSVDDSNRT-SGSKADVIQVRPL   
ENCEPH_fel KSSTVYNPVIYIFMIRKFR RSLLQLLCFRLLRCQRPAKDLPT-NGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVEDSDKT-SVSKVDVIQVRPL   
ENCEPH_can KSSTVYNPVIYIIMIRKFR RSLLQLLCFRPLRCQRPAKDLPA-NGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESVSIDDSDKT-SVSKVDVIQVRPL   
ENCEPH_pte KSSTVYNPVIYIFMIRKFR RFVLQLLCFRPLRCRRPATDLPA-GGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFVITSDESLSVDDSDKI-NGSKADGIQVRPL   
ENCEPH_equ KSSTIYNPIIYIFTIRKFR RSLSQLLCFRLLRCQRPAKDQPP-VGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVHDSDKI-NGSKVEVIQVRPL   
ENCEPH_lox KSSTVYNPVIYTFMIRKFR RSLLQLLCFRLLRCQRPAKDLPV-VGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVNNIDKT-NGSKADVIQIRPL   
ENCEPH_pro KSSTVYNPVIYTFMIRKFR RSLFQLLCFRLLRCQRPAKNKPE-VGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVNDTDKI-NGSKADVIQVRPL   
ENCEPH_cho KSSTVYNLVIYIFMLRKFR RSLLQLLCFRLLRCQRPAKDLPV-VGCEMQIRPIVMSQKEGH---RPKKKVTFNSSSIIFIITSDESISVDGSDKT-NGPKVDVIQVRPL   
ENCEPH_mon KSSTAYNPIIYIFMSRKFR RCLLQLLCFRLLKFQQPKKDRPV-IRTEKQIRPIVMSQKVGD---RPKKKVTFSSSSIIFIITSDETQMIDENDKN-SGTKVNVIQVRPL   
ENCEPH_mac KSSTAYNPIIYIFMSRKFR RCLLQLLCFRQLKFQQPKKDRPV-IRTEKQIRPIVMSQKVGD---RPKKKVTFSSSSIIFIITSDETQMIDDNDKN-NGTKVNVIQVRPL   
ENCEPH_gal KSSTAYNPVIYIFMSRKFR QCLLQLLCFRLMRFQRIMKEPSG-AGNVKPIRPIVMSQKVGD---RPKKKVTFSSSSIIFIIASDDTQQIDDNSKH-NGTKVNVIQVKPL   
ENCEPH_tae KSSTAYNPVIYIFMSRKFR RCLLQLLCFRLMRFQRTMRETPA-TGSDKPIRPIVLSQKAGD---RPKKKVTFSSSSVIFIITSDDAEQIEDSSKH-NETKVNAIQVKPL   
ENCEPH_ano KSSTAYNPVIYIFMSRKFR RCLVQLFCVQFLRFKRTLKEQPA-IESNKPIRPIVMSQKVGD---RPKKKVTFSSSSIIFIITSDDTEQIDVSTKC-SDTKINVIQVKPL   
ENCEPH_dan KSSTAYNPVIYAFMSRKFR RCMLQMLCSRLTSLQHTIKDRPL-SRIEHPIRPIVMSQS--RTD-RPKKRVTFSSSSIVFIIASHDTHPLDITSKCNDEPDINVIQVRPL   
ENCEPH_tak KSSTAYNPLIYVFMSRKFR HCLLQLLCSRLSWLQRSLKERPL-APVQRPIRPIVMSRPCGKGN-RPKKKVTFSSSSIVFIITSDDFGQLDVTSKSGDSADVNAIQVRPL   
ENCEPH_gas KSSTAYNPLICVFMSRKFR RCLMQLLCSRVTCLQCNLKERPL-APVQRPIRPIVVSAACGGGRVRPKKRVTFSSSSIVFIITRNDIRHTDVTSNTRESSEANVFQVRPL   
ENCEPH_ory KSSTAYNPLIYVFMNRKFR RCFLQLLCSKISWLQCTLKEHPL-TPVERPIRPIVASTSCGSRH-RPKKRVTFNSSSIVFMITGDEFQQLDVTSKSRNSSEANVFHVRPL   
ENCEPH_cal KSSTAYNPLIYVFMNRKYR RCLSQLFCSHLMSLQWSIKDPSSKARNDMPVKPIVLSQKGD----RPKKRVTFSSSSIVFIITSDDTQELGSIAGS-NATQISIVQVQPL
Consensus  KSsT.YNPvIyifMiRKFR r.$lQLlC.rllr.qrpaK#.p....emq!rPIVmSqk.gd....RPKKkVTFnSSS!!FiITSD#s.s.dd.dk...gskvdv!QVrPL
             *
ENCEPH_hom KSNTVYNPVIYVFMIRKFR RSLLQLLCLRLLRCQRPAKDLPA AGSEMQIRPIVMSQKDGD---RPKKKVTFNSSSIIFIITSDESLSVDDSDKTNGS-KVDVIQVRPL
ENCEPH_pan ................... ....................... ..................---..................................-..........
ENCEPH_pon ................... ....................... ..................---..................................-..........
ENCEPH_nom ............L...... .........................................---..................................-..........
ENCEPH_mac ................... ....................... ..................---..................................-..........
ENCEPH_pap ................... ....................... ..................---..................................-..........
ENCEPH_cal ................... ..........M....Q.....S. ..................---..................................-..........
ENCEPH_tar ...........I....... .....F.........Q....... .EN...............---...............................S..-..........
ENCEPH_mic ........I..I....... ........F.............. SE................---..........................N....S..-..........
ENCEPH_oto ...........I..L.... ........F.............. .E................---..........................N.......-..........
ENCEPH_tup ..S........I....... ........F....Y......... ..................---K..............................S..-..........
ENCEPH_mus ..S........I..N.... ........F..........N... .E...H............---.........................E...RSSA.-..........
ENCEPH_rat ..S........I....... ........F..........N... .E................---.........................E...RSSA.-..........
ENCEPH_spe ..S........I....... ........S......Q....... V.N........I.....E---.............V..............NR.S..-.A........
ENCEPH_cav ..S.........L...... ......H........Q....... VER..H............---.............................R.S..-...T......
ENCEPH_dip ..S.I......I....... ........F.............. ..................---............................VRSS..-.A........
ENCEPH_ory ..S.A...I..I....... ........FQP....Q.P....T V.................---.................A.....A...NE.AS.P-..........
ENCEPH_fel ..S........I....... ........F.............T N.................---.........................E.....SV.-..........
ENCEPH_can ..S........II...... ........F.P............ N.................---......................V.I......SV.-..........
ENCEPH_pte ..S........I....... .FV.....F.P...R...T.... G.................---...............V..............I...-.A.G......
ENCEPH_equ ..S.I...I..I.T..... ...S....F...........Q.P V.................---.........................H....I...-..E.......
ENCEPH_lox ..S........T....... ........F.............V V.................---.........................NNI......-.A....I...
ENCEPH_pro ..S........T....... ...F....F..........NK.E V.................---.........................N.T..I...-.A........
ENCEPH_cho ..S....L...I..L.... ........F.............V V.C............E.H---......................I...G......P-..........
ENCEPH_mon ..S.A...I..I..S.... .C......F...KF.Q.K..R.V IRT.K..........V..---........S............TQMI.EN..NS.T-..N.......
ENCEPH_gal ..S.A......I..S.... QC......F..M.F..IM.EPSG ..NVKP.........V..---........S........A..DTQQI..NS.H..T-..N....K..
ENCEPH_tae ..S.A......I..S.... .C......F..M.F..TMRET.. T..DKP.....L...A..---........S...V.......DAEQIE..S.H.ET-..NA...K..
ENCEPH_ano ..S.A......I..S.... .C.V..F.VQF..FK.TL.EQ.. IE.NKP.........V..---........S...........DTEQI.V.T.CSDT-.IN....K..
ENCEPH_dan ..S.A......A..S.... .CM..M..S..TSL.HTI..R.L SRI.HP........SRT.---....R...S....V...A.HDTHPL.ITS.C.DEPDIN.......
ENCEPH_tak ..S.A...L.....S.... HC......S..SWL..SL.ER.L .PVQRP.......RPC.KGN-........S....V......DFGQL.VTS.SGD.AD.NA......
ENCEPH_gas ..S.A...L.C...S.... .C.M....S.VTCL.CNL.ER.L .PVQRP.....V.AAC.GGRV....R...S....V....RNDIRHT.VTSN.RE.SEAN.F.....
ENCEPH_cal ..S.A...L.....N..Y..C.S..F.SH.MSL.WSI..PSSK.RND.PVK...L.. .-..---....R...S....V......DTQELGSIAGS.AT-QISIV..Q..

TMT opsin

TMT predominantly exhibits FY for its FR motif though perhaps the conserved FYK/R motif accomplishes the same end. Within the whole TMT family, no observable conservation occurs past the first 9 residues, though some 35 residues are alignable within the sole TMT locus tracking into mammals (marsupials). The conserved pair of cysteines might be palmitoylated. Opossum has acquired an upstream stop codon recently -- the 22 residues following are still alignable to wallaby. GenBank lacks any tetrapod transcripts of this TMT locus as of Jan 09. The last exon of this gene is curiously intertwined with that of the opposing strand gene, the sialyltransferase ST6GAL2. 

TMT_monDom  KSSTVCNPIIYVLMNKQFY KCFLILFHCQPAQSGPDVS LCPSNVTVIQLGQRKNKDA PGSI*DFPEVSEKQLCLLS PEVWPQP                                         
TMT_macEug  KSSTVCNPIIYILMNKQFY KCFLILFHCQPASSASDAS LCPSKMTVIQLGQRKDKEV PCAIQDLPEVSKKQLCLLS PESNVAPSSGHPQEKMEEKPLSE                        
TMT_ornAna  KSSTVCNPIIYILMNKQFY KCFLILFHCQPPRAADAPS TYPSQVMVIQLNQRRSRET AGAPQVLLEMKHQTLHLLG PQLHETPSWERSTPVHPE                              
TMT_taeGut  KSSTVCNPIIYILMNKQFY KCFRQLFHCQPPSSTDGEP TCHSKVTVIQLDQRADGGN MCNNEPHPETDSKMTSLLC PETTSKATPPTS                                    
TMT_galGal  KSSTVCNPIIYILMNKQFY KCFRQLFHCQPPSSTDGEP TCHSKVTVIQLNQKTDGGK LCNNKPRPETDNKVTSLLH PEPGLEPAAKTVPPM                                 
TMT_anoCar  KSSTVFNPIIYILMNKQFY KCFLMLLHCQPSSVADGET ICQSKVMAIHQNQKAQGGV ILKSQVVPQMDEKAICLLS PESSLDPVLESTPQLSKENSFL                         
TMT_xenTro  KSSTVFNPIIYILMNKQFY KCFLILFHCHPTSSADGKS ICQSNYTVIQLNQKLNNIV AIPGQTQIPESVDKMPCIH RQNNESPSDQMPQSTTEHLISGT   
TMT_danRer  KSSTVINPLIYILMNKQFY RCFRILFCCQRSLLQNGHS SMPSKTTVIQLNRRVNSNA VACTAQISTGTHNHDCSTH VTERSNPPEVIP*
TMT_tetNig  KSSTVINPLIYILMNKQFY KCFLILFHCSHWSADNGTT SVPSKITVIQLNRRAYSNT VACADPLSTDALKQCCSAK NASTIEVKLS*
TMT_takRub  KSSTVINPLIYILMNKQFY KCFLILFHCGHWSADNGNT SMPSKTTAIQLNRRVYSNT VACADQLSTDALKQCCSAN TISTKNTSTVEGKLS*
TMT_gasAcu  KSSTVINPLIYILMNKQFY RCFLILFHCKHWSAENHNT SMPSKTTVIHLNRRVCSNT LPCTAQASTDAANHFCSTS ATKHTSPPLQGHGLSLNVLNMIRQENHSHDEAAKNQLDCLT*
TMT_oryLat  KSSTVINPLIYILMNKQFY RCFLILFHCDHWSSENGNT SVPSKTTVIPLNRRIYTNT VAQISTDNAN*
TMT_ictPun  KSSTVINPVIYIFMNKQFY RCFRTLLGYKERSAVPDDH SLMATKNTAIQLKCIMHNN PVPSPAHTPPPFF...
TMT_oncMyk  KSSTVINPLIYILMNKQFY RCFLILFHCKRPSSENGVS SMPSKTTVIQLNRRGHSNN VALTPQLSTGANHHNHNHT VECSTNNREVTTPIGLPHSGWL* 0

TMTa_danRe  KSSTVINPVIYIFMNKQFY RCFRALLNCDKPQRGSSLK SSSKTKPFRPGRRTDNFTF MVASVGPNQTNPVEDGPPSADNTKPAVLSLVAHYNG      
TMTa_takRu  KSSTVINPIIYVFMNKQFY RCFLALLCCQDPRSGSSMK SSSKVATKAKGVTPTGQRR TDFLYMVASLGRPAATIPQLGPSFDATNDFTKPPSSDTIKPVVVSLAAHCDG      
TMTa_tetNi  KSSTVINPVIYVFMNKQFS RCFLSLLCCEDPRSSTSLR SSSRVTTKAVRGGTLTGQR RTNHLLYMVAALGRPVATAMPQLGPSFDATYDITKAPSSDNHQPVVVSLEAHG         
TMTa_gasAc  KTSTVINPVIYVFMNKQFY RCFKALLRCEAPRPSSSLK SSSKVPTKAMRGAAVTGPR HTNNFLFVVASLGRPVATIPQLGPSVEPTIDVTGGPSSDNNKPVIVSLVAQCDG    
TMAa_ictPu  KSSTVINPVIYIFMNKQFY RCFRTLLGYKERSAVPDDS LMATKNTAIQLKCIMHNNP                                                                     
     
TMTb_takRu  KFSTVINPFIYIFMNKQFY RCFRAFLNCSTPKRDSTVR TFTRISLRALRQDQQQKGS ALAPSSARPTPNSIHESSLKGSHSTPSNGGAAAAKSPAANRSKPKLILVAHYRE      
TMTb_tetNi  KFSTVINPFIYIFMNKQFY RCFRAFLSCSSPERGSTVR TFTRISLRAVCQRKQQRVS APAASSACPTPNSIHHSSRKGSHSASSNSGTAAAAKTPAANSSKPKLILVVHYRE      
TMTb_gasAc  KFSTVVNPFIYIFMNKQFY RCFRAFLSCSTPERGSTLK TFSRPTKTLRAGRHEKGRR VSAAAPSTAQPTRNSAPRSSQGANHASATPPPSPADGRCAAAGAAKPKRTLVAHYRE      
TMTb_oryLa  KFSTVINPLIYIFMNKQFY RCFWAFFCCSTPEQVSTLR TFSRVTKTIRTFRQERELH VSAPAPSSGLPTPNSIQKNNHVDPSSINQACAASDSPDSRKPKVVLVAHYQE      
TMTb_pimPr  KTSTVINPIIYIFMNKQFC RCFHALIMCTTPQRGSSFK NSSKVTKTLRTVRRANGQN VTFAVASAGHPTICAPH   
TMTb_danRe  KSSTVINPIIYIFMNKQFC RCFHALIMCTTPERGSSFK NSSKVTKTLRTVRRANGQN VTFAVASAVHRTPYSDRQKSSSEGEKLPPATGQGTSKPVVSLVAYYNG*

TMTcyto.jpg

Imaging ciliary opsins

The cytoplasmic tails of these opsins begin and end with highly conserved motifs but the middle sections have been subject to numerous indels, suggesting that absolute length is unimportant for binding site recognition. The VAPA terminal motif can be recognized in all but the secondary parapinopsin group PPINb (found only in some teleost fish and apparently reflecting differential survival of gene duplication and in avian VAOP where chicken and finch have recent changes in stop codon.

LWS is shown elsewhere greatly expanded to 82 species to illustrate the issues. Four indels, all deletions, have occurred during vertebrate history: a 2 residue loss in mammals, a 1 residue loss in birds but not lizards, and a 1 and 5 residue loss in teleost fish. Otherwise, LWS has been remarkably constant -- its key features and almost every residue past FR were already firmly settled prior to lamprey divergence.

This region cannot be important to Galpha binding because it is too highly variable just within cone opsins which all use the same transducin. Cysteines are conserved to depth but palmitoylation could be universal exclusive of VAOP. LWS also lacks the distal cysteine (CCGK motif has been LFGK since lamprey stem) found in other ciliary opsins. Serines and threonines (for arrestin) are common but are not a deeply conserved feature. 

RHO1_homSa KSAAIYNPVIYIMMNKQFR NCMLTTICCGKNPLGDDE--ASATVSKTETS -----QVAPA
RHO1_bosTa KTSAVYNPVIYIMMNKQFR NCMVTTLCCGKNPLGDDE--ASTTVSKTETS -----QVAPA
RHO1_monDo KSSSVYNPVIYIMMNKQFR TCMITTLCCGKNPLGDDE--ASATASKTETS -----QVAPA
RHO1_ornAn KSSAIYNPVIYIMMNKQFR NCMLTTICCGKNPLGDDE--ASATASKTEQS SVSTSQVSPA
RHO1_galGa KSSAIYNPVIYIVMNKQFR NCMITTLCCGKNPLGDEDTSAG----KTETS SVSTSQVSPA
RHO1_anoCa KSSAIYNPVIYILMNKQFR NCMIMTLCCGKNPLGDEDTSAGT---KTETS TVSTSQVSPA
RHO1_xenTr KSSAIYNPVIYIVLNKQFR NCLITTLCCGKNPFGDEEGSSAA-SSKTEAS SVSSSQVSPA
RHO1_neoFo KTASVYNPVIYILMNKQFR NCMITTLCCGKNPFGDEETTSA-GTSKTEAS SVSSSQVSPA
RHO1_latCh KSASFYNPVIYILLNKQFR NCMITTLCCGKNPFGDEDATSAAGSSKTEAS SVSSSSVSPA
RHO1_takRu KSAALYNPVIYILLNRQFR NCMITTVCCGKNPFGDDDAATTV--SKTQSS SVSSSQVAPA
RHO1_angAn KSSAIYNPLIYICLNSQFR NCMITTLFCGKNPFQEEE-GASTTASKTEAS SVSS--VSPA
RHO1_conMy KSSALYNPMIYICMNKQFR HCMITTLCCGKNPFEEED-GASATSSKTEAS SVSSSSVSPA
RHO1_calMi KSSALYNPLIYILLNKQFR NCMITTLCCGKNPFEEDE-STSAAASKTEAS SVSSSQVSPA
RHO1_leuEr KSSAVYNPLIYILMNKQFR NCMITTICLGKNPFEEEE-STSASASKTEAS SVSSSQVAPA
RHO1_petMa KTSALYNPIIYILMNKQFR NCMITTLCCGKNPLGDEDSGASTS--KTEVS SVSTSQVSPA
RHO1_letJa KSSALYNPVIYILMNKQFR NCMITTLCCGKNPLGDDESGASTS--KTEVS SVSTSQVSPA
RHO1_geoAu KSSALYNPVIYILMNKQFR NCMITTLCCGKNPLGDDDSGASTS--KTEVS SVSTSQVAPA

RHO2_galGa KSSSLYNPIIYVLMNKQFR NCMITTICCGKNPFGDEDVSSTVSQSKTEVS SVSSSQVSPA
RHO2_taeGu KSSSLYNPIIYVLMNKQFR NCMITTICCGKNPFGDEETSSTVSQSKTEVS SVSSSQVSPA
RHO2_podSi KSSSLYNPIIYVLMNKQFR NCMITTICCGKNPFGDDDVSSTVSQSKTEVS SISSSQVSPA
RHO2_anoCa KSSSLYNPIIYVLMNKQFR NCMITTICCGKNPFGDEDVSSSVSQSKTEVS SVSSSQVSPA
RHO2_gekGe KSSSIYNPIIYVLLNKQFR NCMVTTICCGKNPFGDEDVSSSVSQSKTEVS SVSSSQVAPA
RHO2_pheMa KSSCIYNPIIYVLLNKQFR NCMVTTICCGKNPFGDEDASSSVSQSKTEVS SVSSSQVAPA
RHO2_neoFo KSSALYNPIIYVLMNKQFR NCMVTTLCCGKNPFGDDDVSSSVSAGKTEVS SVSSSQVSPA
RHO2_latCh KSSCLFNPIIYVLLNKQFR NCMITTLCCGKNPLGDDDTSSAVSQSKTDVS SVSSSQVSPA
RHO2_takRu KSSALYNPVIYVLLNKQFR NCMLSTIGMGGAV--DDE--TSVSASKTEVS -------SVS
RHO2_gasAc KSSALYNPVIYVLLNKQFR NCMLTTIGMGGMV--EDE--TSVSASKTEVS -------SVS
RHO2_oreNi KSSALYNPIIYVLMNKQFR NCMLSTIGMGGMV--EDE--TSVSTSKTEVS -------SVS
RHO2_hipHi KSSALYNPVIYVLLNKQFR NCMLSTIGMGGMV--EDE--SSVSASKTEVS -------SVS
RHO2_mulSu KSSALYNPVIYVMMNKQFR NCILSAIGMGGMV--EDE--TSVSTSKTEVS -------TAS
RHO2_pomMi KSSALYNPVIYVLMNKQFR NCMLSAVGMGGMV--DDE--TSVSASKTEVS -------SVS
RHO2_oryLa KSSALFNPIIYILLNKQFR NCMLATIGMGGMV--EDE--TSVSTSKTEVS -------TAA
RHO2a_danR KTSAVFNPIIYVLLNKQFR SCMLNTLFCGKSPLGDDE-SSSVSTSKTEVS -----SVSPA
RHO2b_danR KASALFNPIIYVLLNKQFR SCMLNTLFCGKSPLGDDE-SSSVSTSKTEVS -----SVSPA
RHO2c_danR KSSSIFNPIIYVLLNKQFR NCMLTTLFCGKNPLGDDE-SSTVSTSKTEVS -----SVSPA
RHO2d_danR KTSALYNPVIYVLLNKQFR NCMLTTLFCGKNPLGDDE-SSTVSTSKTEVS -----SVSPA
RHO2_calMi KSSVLYNPIIYILMNKQFR SSMITTVCCGKNPFGDDD-SSSVTSQSKTEVSSVSTSQVSPA
RHO2_geoAu KSSVLYNPIIYVLLNKQFR TCMVTTLFCGKNPFGEDD-SSMVSTSKTEVS SVSSSQVSPS

SWS2_ornAn KASTIYNPIIYVFMNKQFR SCMLKLVFCGKSPFGDEDE-ISGSSQATQVS SVSSSQVSPA
SWS2_anoCa KASTVYNPVIYVLMNKQFR SCMLKLIFCGKSPFGDEDD-VSGSSQATQVS SVSSSQVSPA
SWS2_utaSt KASSVYNPVIYVFMNKQFR SCMLKLVFCGKSPFGDEDD-VSGSSQTTQVS SVSSSQVSPA
SWS2_taeGu KASTVYNPIIYVFMNKQFR SCMLKLVFCGRSPFGDEDD-VSGSSQATQVS SVSSSQVSPA
SWS2_neoFo KSSTVYNPLIYVFMNKQFR SCMMKLIFCGKSPFGDEDD-ASSASQSTQVS SVSSSQVAPA
SWS2_galGa KSSTVYNPVIYVLMNKQFR SCMLKLLFCGRSPFGDDED-VSGSSQATQVS SVSSSHVAPA
SWS2_xenTr KASTVYNPFIYIFMNRQFR SCMMKMIFCGKNPLGDDEE--TSVSGSTQVS SVSSSQIAPS
SWS2_takRu KASTVYNPIIYVVLNKQFR SCMKKML---GMSGGDDEE-------SSSQS VTEVSKVSPS
SWS2_gasAc KSSAVYNPVIYVLLNKQFR SCMMKML---GMGGGDDEE-------SSTSS VTEVSKVGPA
SWS2_geoAu KASTVYNPVIYIFLNKQFR SCMMKTIFCGKNPLGDDED---ATSTTTQVS SVSTSQVAPA
SWS1_homSa KSACIYNPIIYCFMNKQFQ ACIMKM-VCGKAMT--DESDTCSS-QKTEVS TVSSTQVGPN
SWS1_monDo KSACVYNPIIYCFMNKQFH ACIMEM-VCRKPMT--DDSDVSSS-QKTEVS AVSSSQVGPT
SWS1_smiCr KSACVYNPIIYCFMNKQFH ACIMEM-ICKKPMT--DDSETTSS-QKTEVS TVSSSQVGPS
SWS1_tarRo KSACVYNPIVYWFMNKQFH ACIMEM-VCRKPMT--DDSEISSS-QKTEVS TVSSSQVGPS
SWS1_taeGu KSSCVYNPIIYCFMNKQFR ACIMET-VCGRPMT--DDSEVSSSAQRTEVS SVSSSQVGPS
SWS1_anoCa KSSCVYNPIIYCFMNKQFR ACILET-VCGKPMS--DESDVSSSAQKTEVS SVSSSQVSPS
SWS1_utaSt KSACVYNPIIYCFMNKQFR ACIMET-VCGKPMT--DESDVSSSAQKTEVS SVSSSQVSPS
SWS1_neoFo KSSFVYNPIIYCFMNKQFR ACIMQT-VFGKPMT--DDSDISSSG-KTEVS SVSSSQVNPS
SWS1_galGa KSACVYNPIIYCFMNKQFR ACIMET-VCGKPLT--DDSDASTSAQRTEVS SVSSSQVGPT
SWS1_xenLa KSSCVYNPIIYSFMNKQFR GCIMET-VCGRPMS--DDSSVSSTSQRTEVS TVSSSQVSPA
SWS1_petMa KASCVYNPLIYSFMNKQFR ARIMET-VCGKFIT--DESETSSS--RTAVS SVSTSQVSPG
SWS1_geoAu KASCVYNPLIYSFMNKQFR ACILET-VCGKPIT--DESETSSS--RTEVS SVSTTQMIPG
SWS1_danRe KSSSVYNPLIYAFMNKQFN ACIMET-VFGKKI---DES--------SEVS SKTETSSVSA
SWS1_oryLa KSSCVYNPLIYAFMNKQFN GCIMEM-VFGKKM---EEA--------SEVS SKTE-VSTDS

LWS_homSap KSATIYNPVIYVFMNRQFR NCILQL--FGKKV---DDGSELSSASKTEVS --SVSSVSPA
LWS_monDom KSATIYNPIIYVFMNRQFR TCILQL--FGKKV---DDGSEVSSTSRTEVS --SVSSVAPA
LWS_ornAna KSATIYNPIIYVFMNRQFR NCIMQL--FGKKV---DDGSELSSTSRTEVS --SVSSVSPA
LWS_galGal KSATIYNPIIYVFMNRQFR NCILQL--FGKKV---DDGSEV-STSRTEVS SVSNSSVSPA
LWS_anoCar KSATIYNPIIYVFMNRQFR NCIMQL--FGKKV---DDGSELSSTSRTEVS SVSNSSVSPA
LWS_xenTro KSATIYNPIIYVFMNRQFR NCIYQL--FGKKV---DDGSEVSSTSRTEVS SVSNSSVSPA
LWS_neoFor KSATIYNPIIYVFMNRQFR NCIYQL--LGKKV---DDGSELSSTSKTEVS SVSNSSVSPA
LWS_takRub KSATIYNPVIYVFMNRQFR VCIMKL--FGKEV---DDGSEV-STSKTEVS -----SVAPA
LWS_gasAcu KSATIYNPVIYVFMNRQFR SCIMQL--FGKEV---DDGSEV-STSKTEVS -----SVAPA
LWS1_calMi KSSTIYNPIIYVFMNRQFR NCILQL--FGKKV---DDGSELSSTSKTDVS SVSNSSVSPA
LWS2_calMi KSSTIYNPIIYVFMNRQFR NCILQL--FGKKV---DDGSELSSTSKTDVS SVSNSSVSPA
LWS_petMar KGATIYNPIIYVFMNRQFR NCILQL--FGKKV---DDGSEVSSSSRTEVS SVSNSSVSPA
LWS_letJap KSATIYNPVIYVFMNRQFR NCIMQL--FGKKV---DDGSEVSSASRTEVS SVSNSSISPA
LWS_geoAus KSATIYNPIIYVFMNRQFR NCIMQL--FGKKV---DDGSEVSSSARTEVS SVSNSSVSPA

PPIN_anoCa KSSTFYNPIIYIFMNKQFR DCLVRCLLCGRNPCA-SEQTDEDDLEVSTIAPAP  SSRRGKVAPV*
PPIN_xenTr KTSTVYNPIIYIFMNKQFQ ECVIPFLFCGRNPWA--AEKSSSMETSISVTSGT  PTKRGQVAPA*
PPIN_ictPu KSSTVFNPIIYIFMNRQFR DYALPCLLCGKNPWA----AKEGRDSDTNTLTTT  VSKNTSVSPL*
PPIN_oncMy KSSTVYNPIIYVFMNRQFR DCAVPFLLCGLNPWA-----SEPVGSEADTALSS  VSKNPRVSPQ*
PPIN_oryLa KSSTVYNPVIYIYLNNQFR RYAVPFLLCGREP---------RDEDEASETTTT  IEITNKVSPS*
PPIN_danRe KSSTVFNPIIYIFMNRQFR DRALPFLLCGRNPWA-----AEAEEEEEETTVSS  VSRSTSVSPA* 
PPINa_takR KSSTVYNPIIYIYLNKQFR KYAVPFLLCGRELEM----------EDELSMTTV  -ETSNRVSPA*
PPINa_tetN KSSTAYNPIIYIYLNKQFR KYALPFLLCRRALEA----------EDEVSETTV  -ESSRRVSPS*
PPINa_gasA KSSTVFNPIIYIYLNKQFR KYAVPFLLCCKEPLD--------DEEASEAATTV  EISPSKVSPA*
PPIN_petMa KTSTVYNPIIYIFMNRQFR DCAVPFLLCGRNPWAEPSSESATTASTSATSVTL  ASVPGQVSPS*
PPIN_letJa KTSTVYNPIIYIFMNRQFR DCAVPFLLCGRNPWAEPSSESATAASTSATSVTL  ASAPGQVSPS*
PPINa_cioI KTATIYNPLIYIGLNRQFR DCVVRMIFNGRNPWV---DELVGSQVSSTGSQLT  AVSSNKVAPA*
PPINa_cioS KTATIYNPLIYIGLNRQFR DCVVRMIFNGRNPWV---DEMVGSQVSSSASQMT  AVSSNKVAPA*

PPINb_gasA KSSTVYNPIIYIFMNRQFR GYAVPSILCGWNPWA--EEQTSEEETVGSVMKSQ RVSPKGSLQE*
PPINb_tetN KSSTVYNPIIYVFMNRQFR GYAINTILCGRRAWVSEQQTSEGETTVVSVSKSQ KISPKGSLQ*
PPINb_takR KSSTVYNPIIYIFMNRQFR GCAINTVLCGRRAWITDLQTSEGETTVASTSKSQ KISPKGSLN* 
PPINb_mayZ KSSTVYNPIIYIFMNRQFR GYTVAAVLCGWDPWSSEPQTSENETTVPFFIKTPKKIVPKKSLE*

PARIE_anoC KTSPVYNPIIYIFLNKEFR ECAVEFITCGKVVLTSPEEDISTSAISDEGIA--     PCKINQVTPV*
PARIE_utaS KTSPVYNPIIYIFLNKQFR DCAVEFITCGQVVLTSPEEDISTSAIPVEGKG--     PCKINQVTPV*
PARIE_xenT KTSPVYNPIIYIFLNKQFR TYAVQCLTCGHINLDSLEEDTESVSAQAENML--     TPKTNQVAPA*
PARIE_takR KTSPVYNPIIYFLSNKQFR DATLEVLSCSRYIPHASSRVSINMRSLNRRS---     VNTHSKVSPL*
PARIE_tetN KTSPVYNPIIYFLSNKQFR DATLEVLSCGRYIPHASTRVTFNMCAFNRRSRLPSLSRSINTHSKVSPL*
PARIE_gasA KTSPVYNPIIYFLSNKQFR DAALEMLSCGRYIAHMPNTVSINMRSLNRRSRLSSLSRNVNSHSKVLPL*   
PARIE_danR KTSPVYNPIIYFLTNKRFR ESSLEVLSCGRYISRETGGPLMGSSM--------     QRGQSRVNPV*

PIN_galGal KTATVYNPIIYVFMNKQFQ SCLLEMLCCGYQPQRTGKASPGTPGPHA-DVT--AA GLRNKVMPA HPV*
PIN_colLiv KTATVYNPIIYVFMNKQFQ SCLLKMLCCGHHPRGTGRTAPAAPASPT-D------ GLRNKVTPS HPV*
PIN_taeGut                  FQ SCLLGMLCCGHHPRGMGKTSPAAPSP-----QVAAE GLRNKVTPS HPV*
PIN_utaSta KTATVYNPIIYVFMNKQFR SCLLSTMSCGHRPRGAQETTPAMISIPQGP-TSALQ GSRNKVTPS ASEGSGNEAIPS*
PIN_podSic KTATVYNPIIYVFMNKQFR SCLLYKMSCGHRALSSQDTTPAGISLPGRLTTSASK GSRNQVSPS*
PIN_pheMad KTATVYNPIIYVFMNKQFR SCLLNTVSCGRIPQTMPGTPATTAVRGGFVLTSE-- GRGNKVAST ELHS*
PIN_xenTro KTATVYNPIIYVFMNKQFR NCLMTLLCCGRS-FGDDETSSA---SGRTDVTSVSE AGGNKVTPA*
PIN_xenlae KTATVYNPIIYVFMNKQFR NCLMTLLCCGRSPFGDDETSTS---SARTDVTSVSK AGGNKVTPA*
PIN_bufJap KTATVYNPVIYVFMNKQFR DCLTKLLCCGRNPFGEDETSTT---SGRTDVTSVSE GGGNKVTPA*

VAOP_galGa KTATVYNPIIYVFMNKQFR MCLIQMFKCSAIETAESNMNPTSERATLTQDKRDSQLSVMAVRSTIS*
VAOP_taeGu KTATVYNPVIYVFMNKQFR QCLIQMFSCSAIGTAESNMKLTSERAVLMQGRRGSKRTPMAVHSTVLKRKTGDEHRADDLWLF*
VAOP_anoCa KTATVYNPVIYVFMNNQFR KCLVQLFQCSSQETMDANVNPISEKDTLTHTKHCGEMSTVAAHVI---VFNPRSEDEQGSCQSFAQLAISENKVYPL*
VAOP_xenTr KTASMYNPIIYVYMNKQFR RCLYQMFNINDPEAKESNLNPTSERGVLTRNNNGGEMLAIATHIT--SSAVTNREEEKSSSNSFAHIPVSDNKVCPM*
VAOP_danRe KTAAVYNPIIYVFMNKQFR KCLVQLLSCSKVTVVEGNNNQTTERAGMTSGSNTGEMSAIAARVS-----VPKTEENPGDRSTFSHIPIPENKVCPM*
VAOP_takRu KTAAVYNPIIYVFMNKQFR KCLIQHFIGMGVMA-ESNMNPTSERPGITAESQTGEMSAIAARVPVGATAALHSDGSPTDCGSLAQLPIPENKVCPI*
VAOP_rutRu KTAAVYNPVIYVFMNKQFR KCLVQLLRCRDVTIIEGNINQTSERQGMTNESHTGEMSTIASRIPKDGSIPEKTQEHPGERRSLAHIPIPENKVCPM*
VAOP_petMa KTATVYNPVIYIFMNKQFR DCFVQVLPCKGLKKVSATQTAGAQDTEHTASVNTQSPGNRHNIALAAGSLRFTGAVAPSPATGVVEPTMSAAGSMGAPPNKSTAPCQQQGQQQQQQGTPIPAITHVQPLLTHSESVSKICPV*

Reference sequence collection

Cytoplasmic loop C2 from 101 melanopsins

species    helix bridge area  hel transmemb Le 7 9
MEL1_homSa DRYLV ITRPLATFGVAS KRR AAFVLLGVW 20 T P
MEL1_panTr DRYLV ITRPLATFGVAS KRR AAFVLLGVW 20 T P
MEL1_gorGo DRYLV ITRPLATFGVAS KRR AAFVLLGVW 20 T P
MEL1_ponAb DRYLV ITRPLATIGVAS KRR AAFVLLGVW 20 T P
MEL1_rheMa DRYLV ITRPLATIGVAS KRR AAFVLLGVW 20 T P
MEL1_calJa DRYLV ITRPLATIGVAS TKR AAFVLLGVW 20 T P
MEL1_micMu DRYLV ITRPLASVGTAS KRR AGLVLLGVW 20 T P
MEL1_otoGa DRYLV ITRPLTTVGVAS KRR AALVLLGVW 20 T P
MEL1_musMu DRYLV ITRPLATIGRGS KRR TALVLLGVW 20 T P
MEL1_ratNo DRYLV ITRPLATIGMRS KRR TALVLLGVW 20 T P
MEL1_nanEh DRYLV ITRPLATIGVAS KRR TALVLLGVW 20 T P
MEL1_phoSu DRYLV ITRPLATIGMGS KRR TALVLLGIW 20 T P
MEL1_dipOr DRYLV ITRPLATIGVTS KRR TAFVLLGVW 20 T P
MEL1_cavPo DRYLV ITRPLATIGVAS KRQ AALVLLGVW 20 T P
MEL1_speTr DRYLV ITRPLATIGMAS KKR AAFFLLGVW 20 T P
MEL1_oryCu DRYLV ITRPLAAVGMVS KKR AGLVLLGVW 20 T P
MEL1_ochPr DRYLV ITRPLAAVGMVS KRR TGLVLLGVW 20 T P
MEL1_bosTa DRYLV ITRPLATVGMVS KRR AALVLLGVW 20 T P
MEL1_turTr DRYLV ITRPLATVGMVS KRR AALVLLGVW 20 T P
MEL1_susSc DRYLV ITHPLATVGMVS KRR AALVLLGVW 20 T P
MEL1_equCa DRYLV ITRPLATVGVVS KRW AALVLLGIW 20 T P
MEL1_felCa DRYLV ITHPLATIGVVS KRR AALVLLGVW 20 T P
MEL1_canFa DRYLV ITHPLAAVGVVS KRR AALVLLGVW 20 T P
MEL1_myoLu DRYLV ITRPLA-IGVVS KRR AALVLLGVW 19 T P
MEL1_pteVa DRYLV ITRPLAAIGVVS KRR AALVLLGVW 20 T P
MEL1_eriEu DRYLV ITRPLATIGVVS KRR VALVLLGVW 20 T P
MEL1_loxAf DRYLV ITRPLATIGVVS KRR AALVLLGIW 20 T P
MEL1_proCa DRYLV ITRPLATIGVVS KRR TALVLLGTW 20 T P
MEL1_echTe DRYLV ITRPLATIGVVS KRR AALVLLVIW 20 T P
MEL1_smiCr DRYFV ITRPLASIGMIS KKK TGLILLGVW 20 T P
MEL1_monDo DRYFV ITRPLASIGVIS KKK TGFILLGVW 20 T P
MEL1_ornAn DRYFV ITRPLASIGVIS KKR ALLILTGVW 20 T P
MEL1_anoCa DRYFV ITRPLASIGAMS TKK ALLILSGVW 20 T P
MEL1_taeGu DRYFV ITKPLASVGVTS KKK ALIILVGVW 20 T P
MEL1_galGa DRYFV ITKPLASVRVMS KKK ALIILVGVW 20 T P
MEL1_xenTr DRYFV ITRPLTSIGVMS KKR AVLILSGVW 20 T P
MEL1_danRe DRYFV ITRPLASIGVLS QKR ALLILLVAW 20 T P
MEL1_danRe DRYFV ITRPLASIGVMS RKR ALLILSAAW 20 T P
MEL1_takRu DRYFV ITRPLTSIGVLS RKR AFVILMTVW 20 T P
MEL1_gasAc DRYFV ITRPLTSIGMMS RRR ALLILMGAW 20 T P
MEL1_oryLa DRYFV ITRPLTSIGVLS RKR ALLILSAAW 20 T P
MEL1_calMi DRYFV ITRPLASIGVLS HRR AGLIILSLW 20 T P
MEL1_petMa DRYLV LTRPLASIGAMS KRR AMYITAAVW 20 T P
MEL2_galGa DRYLV ITKPLRSIQWTS KKR TIQIIAAVW 20 T P
MEL2_anoCa DRYCV ITKPLQSIKRTS KKR TCIIIVFVW 20 T P
MEL2_xenLa NRYIV ITKPLQSIQWSS KKR TSQIIVLVW 20 T P
MEL2_danRe DRYLV ITKPLQTIQWNS KRR TGLAILCIW 20 T P
MEL2_tetNi DRYVV ITKPLQTIRRSS KRR TALAILMVW 20 T P
MEL2_gasAc DRYLV ITKPLQAIHWGS KRR TTLAILLVW 20 T P
MEL1_plaDu DRFYV ITNPLGAAQTMT KKR AFIILTIIW 20 T P
MEL1_capCa DRYMV IAKPFYAMKHVS HKR SLIQIILAW 20 A P
MEL1_helRo DRYLV VGQPLAMLNQSH FRR SFYHVLIIW 20 G P
MEL1_todPa DRYNV IGRPMAASKKMS HRR AFIMIIFVW 20 G P
MEL1_schMe DRYFV IAQPFQTMKSLT IKR AIIMLVFVW 20 A P
MEL2_schMa DRYLV IATPFESVFQTT PRR TLLLMLFLW 20 A P
MEL1_lotGi DRYLV ITSPFTAMRNMT HKR AFLMIVGVW 20 T P
MEL1_sepOf DRYNV IGRPMAASKKMS HRR AFLMIIFVW 20 G P
MEL1_entDo DRYNV IGRPMAASKKMS HRR AFLMIIFVW 20 G P
UVV_camAb  DRYST IARPLDGKLS   RGQ VLLLIMLIW 18 A P
UVV_catBo  DRYST IARPLDGKLS   RGQ VILLIALIW 18 A P
UVV_apiMe  DRYST IARPLDGKLS   RGQ VILFIVLIW 18 A P
BLU_apiMe  DRYRT ISCPIDGRLN   SKQ AAVIIAFTW 18 S P
BLU_ DRoMe DRYKT ISNPIDGRLS   YGQ IVLLILFTW 18 S P
BLU_manSe  DRYKT ISSPLDGRIN   TVQ AGLLIAFTW 18 S P
UVV1_droMe DRYNV ITKPMNRNMT   FTK AVIMNIIIW 18 T P
UVV1_pedHu DRCET ITNPL-QKSG   KKK AFLLAAFTW 18 T P
UVV_manSe  DRHST ITRPLDGRLS   EGK VLLMVAFVW 18 T P
UVV_papXu  DRHST ITRPLDGRLS   RGK VLLMMVCVW 18 T P
UVV2_droMe DRFNV ITRPMEGKMT   HGK AIAMIIFIY 18 T P
UVV2_pedHu DRYQV IVHPLER-KT   KAA VYFQILLIW 18 V P
LWS_nemVe  DRYIV IVHPMKKIMT   RKK AALMIVGVW 18 V P
LWS_pedHu  DRYNV IVKGLSAKPMT  IKM ALLNILFVW 19 V G
LWS_vanCa  DRYNV IVKGIAAKPLT  ING AMLRVLGIW 19 V G
LWS_papXu  DRYNV IVKGIAAKPMT  ING ALLRILGIW 19 V G
LWS_helSa  DRYNV IVKGIAAKPMT  ING ALLRVFGIW 19 V G
LWS_pieRa  DRYNV IVKGIAAKPMT  INS ALLRILGVW 19 V G
LWS_manSe  DRYNV IVKGIAAKPMT  SNG ALLRILGIW 19 V G
MWS2_droMe DRYNV IVKGINGTPMT  IKT SIMKILFIW 19 V G
LWS_rhoPr  DRYNV IVKGISAKPMT  NKT AMLRILLVW 19 V G
LWS_meoOe  DRYNV IVKGISGTPLS  QKN TTLQVLFVW 19 V G
LWS_catBo  DRYNV IVKGLSAKPMT  ING ALLRILGIW 19 V G
LWS_schGr  DRYNV IVKGLSAKPMT  NKT AMLRILFIW 19 V G
LWS_triCa  DRYNV IVKGLSAQPLT  KKG AMLRILIIW 19 V G
LWS2_apiMe DRYNV IVKGLSGKPLS  ING ALIRIIAIW 19 V G
LWS_bomTe  DRYNV IVKGLSGKPLT  ING ALLRILGIW 19 V G
MWS_calEr  DRYNV IVKGMAGQPMT  IKL AIMKIALIW 19 V G
MWS1_droMe DRYQV IVKGMAGRPMT  IPL ALGKIAYIW 19 V G
LWS_droMe  DRYCV IVKGMARKPLT  ATA AVLRLMVVW 19 V G
LWS_arcGr  DRYNV IVKGVAAEPLT  SKG ASIRILFVW 19 V G
LWS_eupSu  DRYNV IVKGVAATPLT  NKG AFARNIFSW 19 V G
LWS_camLu  DRYNV IVKGVAGEPLS  TKK ASLWILTVW 19 V G
LWS_proMi  DRYNV IVKGVAGEPLS  TKK ASLWILIVW 19 V G
LWS_holCo  DRYNV IVKGVSAEPLT  SGG AMMRIAGTW 19 V G
LWS_homGa  DRYNV IVKGVSATPLT  TNG AMLRNLFSW 19 V G
LWS_neoAm  DRYNV IVKGVSGEPLT  NSG AMTRIAGTW 19 V G
LWS_neoOe  DRYNV IVKGVSGKPLS  QKN ATLQVLFVW 19 V G
LWS_mysDi  ERYNV IVKGVSSKPLS  VKG AITRIVLTW 19 V G
LWS1_apiMe DRYNV IVKGMSGTPLT  IKR AMLQILGIW 19 V G
LWS_limPo  DRYNV IVRGMAAAPLT  HKK ATLLLLFVW 19 V G
LWS_limPo  DRYNV IVRGMAAAPLT  HKK ATLLLLFVW 19 V G
LWS_ixoSc  DRYNV IVRGVAAAPLT  HKR AALMIFFVW 19 V G
ADRB2_homS DRYFA ITSPFKYQSLLT KNK ARVIILMVW 20 T P
ADRA2A_hom DRYWS ITQAIEYNLKRT PRR IKAIIITVW 20 T A
ADRA2C_hom DRYWS VTQAVEYNLKRT PRR VKATIVAVW 20 T A
HTR1A_homS DRYWA ITDPIDYVNKRT PRR AAALISLTW 20 T P
CHRM1_homS DRYFS VTRPLSYRAKRT PRR AALMIGLAW 20 T P
DRD2_homSa DRYTA VAMPMLYNTRYS KRR VTVMISIVW 21 A P
TAAR9_homS DRYIA VTDPLTYPTKFT VSV SGICIVLSW 20 T P
ADRA2B_hom DRYWA VSRALEYNSKRT PRR IKCIILTVW 20 S A

Reference collection of 377 cytoplasmic loop C2 sequences from all 20 opsin loci

The second column contains the C2 loop sequences. The third column shows the continuation into transmembrane helix 4. The end of the loop region is determined by countback from the invariant tryptophan at position 160 in squid melanopsin as well as from crystallography and transmembrane prediction tools. Other columns show loop length and values at potentially informative positions 7 and 9 (which are generally characteristic of orthology class). 

RHO1_homSa	ERYVVVCKPMSNFRFGENH	AIMGVAFTW	19	C	P
RHO1_bosTa	ERYVVVCKPMSNFRFGENH	AIMGVAFTW	19	C	P
RHO1_ornAn	ERYIVVCKPMSNFRFGENH	AIMGVAFTW	19	C	P
RHO1_monDo	ERYVVVCKPMSNFRFGENH	AIIGVAFTW	19	C	P
RHO1_galGa	ERYVVVCKPMSNFRFGENH	AIMGVAFSW	19	C	P
RHO1_calMi	ERYVVVCKPMSNFRFGTNH	AIMGVAFTW	19	C	P
RHO1_xenTr	ERYVVVCKPMANFRFGENH	AIMGVVFTW	19	C	P
RHO1_latCh	ERYVVVCKPMSNFRFGENH	AIMGVIFTW	19	C	P
RHO1_neoFo	ERYIVVCKPISNFRFGENH	AIMGVVFTW	19	C	P
RHO1_angAn	ERWVVVCKPMSNFRFGENH	AIMGLAFTW	19	C	P
RHO1_takRu	ERYIVVCKPMTNFRFGEKH	AIAGLVFTW	19	C	P
RHO1_leuEr	ERYMVVCKPMANFRFGSQH	AIIGVVFTW	19	C	P
RHO1_petMa	ERYIVICKPMGNFRFGSTH	AYMGVAFTW	19	C	P
RHO1_letJa	ERYIVICKPMGNFRFGNTH	AIMGVAFTW	19	C	P
RHO1_geoAu	ERYIVICKPMGNFRFGNTH	AIMGVALTW	19	C	P
RHO2_galGa	ERYIVVCKPMGNFRFSATH	AMMGIAFTW	19	C	P
RHO2_gekGe	ERYIVICKPMGNFRFSATH	AIMGIAFTW	19	C	P
RHO2_anoCa	ERYIVVCKPMGNFRFSATH	ALMGISFTW	19	C	P
RHO2_taeGu	ERYIVICKPMGNFRFSASH	ALMGIAFTW	19	C	P
RHO2_podSi	ERYIVVCKPMGNFRFSSSH	ALMGIAFTW	19	C	P
RHO2_pheMa	ERYIVICKPMGNFRFSSSH	AMMGISFTW	19	C	P
RHO2_latCh	ERYIVVCKPMGNFRFASSH	AIMGIAFTW	19	C	P
RHO2_neoFo	ERYIVVCKPMGNFRFSNNH	SIIGIVFTW	19	C	P
RHO1_anoCa	ERYVVICKPMSNFRFGETH	ALIGVSCTW	19	C	P
RHO1_conMy	ERWMVVCKPVTNFRFGESH	AIMGVMVTW	19	C	P
RHO2_ancDa	ERYIVVCKPMGSFKFSSSH	AMAGIAFTW	19	C	P
RHO2a_danR	ERYIVVCKPMGSFKFSANH	AMAGIAFTW	19	C	P
RHO2b_danR	ERYIVVCKPMGSFKFSSNH	AMAGIAFTW	19	C	P
RHO2c_danR	ERYIVVCKPMGSFKFSSNH	AFAGIGFTW	19	C	P
RHO2d_danR	ERYIVVCKPMGSFKFSASH	AFAGCAFTW	19	C	P
RHO2_oryLa	ERYIVVCKPMGSFKFTATH	SAAGCAFTW	19	C	P
RHO2_takRu	ERYVVVCKPMGSFKFTGTH	AAVGVAFTW	19	C	P
RHO2_gasAc	ERYIVVCKPMGSFKFSGTH	AGAGVLFTW	19	C	P
RHO2_hipHi	ERYIVVCKPMGSFKFSGTH	AGIGVLFTW	19	C	P
RHO2_mulSu	ERYIVVCKPMGSFKFSGTH	AGAGVAFTW	19	C	P
RHO2_oreNi	ERYIVVCKPMGSFKFTGAH	AGAGVLFTW	19	C	P
RHO2_pomMi	ERYIVVCKPMGSFKFSGAH	AGAGVALTW	19	C	P
RHO2_calMi	ERYVVVCKPMSNFRFGTSH	ALMGMGFTW	19	C	P
RHO2_geoAu	ERYIVVCKPMGNFRFATTH	AALGVVFTW	19	C	P
SWS2_ornAn	ERFLVICKPLGNLSFRGTH	AIFGCAATW	19	C	P
SWS2_anoCa	ERYLVICKPLGNFTFRGTH	AIIGCAVTW	19	C	P
SWS2_utaSt	ERFLVICKPLGNFSFRGTH	AIIGCIITW	19	C	P
SWS2_taeGu	ERFLVICKPLGNFTFRGSH	AVLGCAITW	19	C	P
SWS2_galGa	ERFLVICKPLGNFTFRGSH	AVLGCVATW	19	C	P
SWS2_neoFo	ERFLVICKPLGNFTFRSTH	AIIGCVATW	19	C	P
SWS2_xenTr	ERFLVICKPMGNFTFRESH	AVLGCILTW	19	C	P
SWS1_homSa	ERYIVICKPFGNFRFSSKH	ALTVVLATW	19	C	P
SWS1_monDo	ERFIVICKPFGNFRFNSKH	AMMVVLATW	19	C	P
SWS1_smiCr	ERFIVICKPFGNFRFNSKH	AMMVVLATW	19	C	P
SWS1_tarRo	ERFIVICKPFGNFRFSSKH	AMMVVLATW	19	C	P
SWS1_taeGu	ERYIVICKPFGNFRFNSRH	ALLVVAATW	19	C	P
SWS1_anoCa	ERYIVICKPFGNFRFNSRH	ALLVVAATW	19	C	P
SWS1_utaSt	ERYIVICKPFGNFRFNSKH	ALLVVAATW	19	C	P
SWS1_galGa	ERYIVICKPFGNFRFSSRH	ALLVVVATW	19	C	P
SWS1_geoAu	ERYIVICKPFGNFRFGSKH	ALVAVGLTW	19	C	P
SWS1_neoFo	ERYLVICKPIGNFRFGSKH	SMIAVVAAW	19	C	P
SWS1_xenLa	ERYIVICKPMGNFNFSSSH	ALAVVICTW	19	C	P
SWS1_petMa	ERYIVICKPFGNFRFGSIH	SLFAFCLTW	19	C	P
SWS1_danRe	ERYVVICKPFGSFKFGQGQ	AVGAVVFTW	19	C	P
SWS1_oryLa	ERYLVICKPFGAFKFGSNH	ALAAVIFTW	19	C	P
SWS2_geoAu	ERCLVICKPFGNIAFRGTH	ALIRCGFAW	19	C	P
SWS2_takRu	ERWLVVCKPLGNFIFKPDH	AIVCCIFTW	19	C	P
SWS2_gasAc	ERWLVICKPLGNFIFKPDH	ALVCCAFTW	19	C	P
LWS_homSap	ERWMVVCKPFGNVRFDAKL	AIVGIAFSW	19	C	P
LWS_monDom	ERWVVVCKPFGNVKFDAKL	AMVGIIFSW	19	C	P
LWS_ornAna	ERWIVVCKPFGNVKFDAKL	AMVGIVFSW	19	C	P
LWS_anoCar	ERWVVVCKPFGNVKFDAKL	AVAGIVFSW	19	C	P
LWS_galGal	ERWFVVCKPFGNIKFDGKL	AVAGILFSW	19	C	P
LWS_xenTro	ERWFVVCKPFGNIKFDGKL	AATGIIFSW	19	C	P
LWS_neoFor	ERWVVVCKPFGNIKFDGKW	AAGGIIFSW	19	C	P
LWS_calMil	ERWVVVCKPFGNVKFDGKW	AAFGIIFSW	19	C	P
LWS_takRub	ERWVVVCKPFGNVKFDAKW	ATGGIVFSW	19	C	P
LWS_gasAcu	ERWIVVCKPFGNVKFDAKW	ATAGIVFSW	19	C	P
LWS1_calMi	ERWVVVCKPFGNMKFDSKM	AVAGIVFSW	19	C	P
LWS2_calMi	ERWVVVCKPFGNVKFDGKW	AAFGIIFSW	19	C	P
LWS_petMar	ERWMVVCKPFGNIKFDGKI	ATILIVFSW	19	C	P
LWS_letJap	ERWMVVCKPFGNIKFDGKI	AIILIVFSW	19	C	P
LWS_geoAus	ERWMVVCKPFGNLKFDGKV	AIVLIIFSW	19	C	P
PIN_galGal	ERYVVVCRPLGDFQFQRRH	AVSGCAFTW	19	C	P
PIN_pheMad	ERYLVICKPVGDFQFQRRH	AVIGCLYTW	19	C	P
PIN_utaSta	ERYLVICKPVGDFRFQQRH	AVFGCVFTW	19	C	P
PIN_xenTro	ERYLVICKPMGDFRFQQKH	AILGCSFTW	19	C	P
PIN_bufJap	ERYIVICKPMGDFRFQQRH	AVMGCAFTW	19	C	P
PIN_podSic	ERYLVICKPVGDFRFPARH	AVLGCAFTW	19	C	P
PIN_calMil	ERYIVICKPMGDFRFQQKH	AVWGCLFTW	19	C	P
VAOP_galGa	ERYIVICRPVGNMRLRGKH	AAQGIAFVW	19	C	P
VAOP_anoCa	ERYVVICRPLGNMRLNGKH	AALGVAFVW	19	C	P
VAOP_xenTr	ERYIVICRPLGNLRLQGKH	SALAIIFVW	19	C	P
VAOP_danRe	ERFFVICRPLGNIRLRGKH	AALGLVFVW	19	C	P
VAOP_rutRu	ERFFVICRPLGNIRLRGKH	AALGLLFVW	19	C	P
VAOP_takRu	ERFFVICRPLGNMRLQAKH	AAIGLLFVW	19	C	P
VAOP_petMa	ERYFVICRPLGNFRLQSKH	AVLGLAVVW	19	C	P
PPIN_anoCa	DRAIVIAKPMGTITFTTRK	AMIGVAVSW	19	A	P
PPIN_xenTr	DRVFVVCKPMGTLTFTPKQ	ALAGIAASW	19	C	P
PPIN_ictPu	DRYMVVCRPLGAVMFQTKH	ALAGVVFSW	19	C	P
PPIN_oncMy	DRYVVVCRPMGAVMFQTRH	AVGGVVLSW	19	C	P
PPIN_danRe	ERCMVVCRPVGSISFQTRH	AVFGVAVSW	19	C	P
PPIN_petMa	DRFVVVCKPLGTLMFTRRH	ALLGITWAW	19	C	P
PPIN_letJa	DRFVVVCKPLGTLMFTRRH	ALLGIAWAW	19	C	P
PPIN2_petM	ERYVVVCKPLGGVHFGTQH	GLCGVAISW	19	C	P
PARIE_utaS	ERYNVVCQPLGTLQMSTKR	GYQLLGFIW	19	C	P
PARIE_anoC	ERYNVVCQPLGTLQMSTQR	AYQLLGFIW	19	C	P
PARIE_xenT	ERYNVVCEPIGALKLSTKR	GYQGLVFIW	19	C	P
PARIE_takR	ERYNVVCKPRAGLKLTMRR	SIIGLLFVW	19	C	P
PARIE_gasA	ERYNVVCRPRNALKLSMRR	SIHGLLIVW	19	C	P
PARIE_danR	ERYNVVCKPMAGFKLNVGR	SCQGLLLVW	19	C	P
PER_homSap	DRYLTICLPDVGRRMTTNT	YIGLILGAW	19	C	P
PER_panTro	DRYLTICLPDVGRRMTTNT	YIGLILGAW	19	C	P
PER_nomLeu	DRYLTICLPDVGRRMTTNT	YIGLILGAW	19	C	P
PER_gorGor	DRYLTICLPDVGRRMTTNT	YIGLILGAW	19	C	P
PER_ponPyg	DRYLTICLPDIGRRMTTNT	YIGLILGAW	19	C	P
PER_macMul	DRYLTICLPDIGRRMTTNT	YIGMILGAW	19	C	P
PER_papHam	DRYLTICLPDIGRRMTTNT	YIGMILGAW	19	C	P
PER_otoGar	DRYLTICRPDIGRRMTTNS	YIGMILGAW	19	C	P
PER_tarSyr	DRYLTICRPDIGRRMTTNT	YVGMILGAW	19	C	P
PER_micMur	DRYLTICRPDIGRRMTTHT	YVGMILGAW	19	C	P
PER_cavPor	DRYLTICRPDIGRRMTSHS	YVGMILGAW	19	C	P
PER_ochPri	DRYLTICQPDIGRRMTTHT	YFGMILGAW	19	C	P
PER_oryCun	DRYLTICHPDVGRRMTTRT	YLGLILGAW	19	C	P
PER_calJac	DRYLTICLPDIGRRMTTST	YIIMILGAW	19	C	P
PER_canFam	DRYLTICSPDTGRRMTTNT	YISMILGAW	19	C	P
PER_felCat	DRYLTICSPNSGRRMTTNT	YISMILGAW	19	C	P
PER_susScr	DRYLTICRPEAGRRMTTNT	YISMILGAW	19	C	P
PER_vicVic	DRYLTICRPDAGRRMTTNT	YISMILGAW	19	C	P
PER_turTru	DRYLTICCPGAGRRMTTNT	YISMILGAW	19	C	P
PER_bosTau	DRYLTICHPDAGRRMTANT	YISMILGAW	19	C	P
PER_choHof	DRYLTICHPDVGRRMTINT	YISMILGAW	19	C	P
PER_dasNov	DRYLTICRPDTGRRMTINT	YISMILGAW	19	C	P
PER_echTel	DRYLTICHPDRGRRMTSNT	YVGMILGAW	19	C	P
PER_loxAfr	DRYLTICHPHIGRRMTSNT	YVSMILGAW	19	C	P
PER_sorAra	DRYLTLCRPDAGRSMTTNS	YVGLILGAW	19	C	P
PER_equCab	DRYLTTCRPDAGRRMTTST	YTSMILGAW	19	C	P
PER_dipOrd	DRYLTICHPDIGRGMTTRT	YVTMILGAW	19	C	P
PER_musMus	DRYLTISCPDVGRRMTTNT	YLSMILGAW	19	S	P
PER_ratNor	DRYLTISCPDVGRRMTGNT	YLSMVLGAW	19	S	P
PER_eriEur	DRYLTICRPHTGRSMSANS	YIAMILGAW	19	C	P
PER_tupBel	DRYLTLCRPAVGRRMGSST	YAAMILGAW	19	C	P
PER_monDom	DRYLTICQPDLGGRMTSYN	YTLMILTAW	19	C	P
PER_ornAna	DRYLTICRPAIGRKMTRSN	YTAMILAAW	19	C	P
PER_xenTro	DRYLTICRPDIGRRISGRH	YTAMILAAW	19	C	P
PER_galGal	DRYLTICRPDIGRRMTTRN	YAALILAAW	19	C	P
PER_anoCar	DRYLTICKPHIGSRLTATN	YTTLILAAW	19	C	P
PER_taeGut	DRYLTICRPDIGRRMTTRS	YATLILAAW	19	C	P
PER1_gasAc	DRYLTICRPDIGQKMTMQS	YNLLILAAW	19	C	P
PER_gasAcu	DRYLTICRPDIGQKMTMQS	YNLLILAAW	19	C	P
PER_oryLat	DRYLTICRPDLGQKMTMQS	YNLLILAAW	19	C	P
PER_takRub	DRYITICRPDIGRKMTVQS	YNLLILAAW	19	C	P
PER_tetNig	DRYLTICRPDIGRKMTVQS	YNLLIAAAW	19	C	P
PER_danRer	DRYLTICRPDIGQKLTTRS	YTLLIVAAW	19	C	P
PER1a_sacK	DRYWATCSPVEVMELKSKY	YTRMTALGW	19	C	P
NEUR1_homS	DRYLKICYLSYGVWLKRKH	AYICLAAIW	19	C	L
NEUR1_nomL	DRYLKICYLSYGVWLKRKH	AYICLAAIW	19	C	L
NEUR1_panT	DRYLKICYLSYGVWLKRKH	AYICLAAIW	19	C	L
NEUR1_ponP	DRYLKICYLSYGVWLKRKH	AYICLAAIW	19	C	L
NEUR1_macM	DRYLKICYLSYGVWLKRKH	AYICLAAIW	19	C	L
NEUR1_papH	DRYLKICYLSYGVWLKRKH	AYICLAAIW	19	C	L
NEUR1_calJ	DRYLKICYLSYGVWLKRKH	AYICLAAIW	19	C	L
NEUR1_tarS	DRYLKICYLSYGVWLKRKH	AYICLAAIW	19	C	L
NEUR1_cavP	DRYLKICYLSYGVWLKRKH	AYICLAAIW	19	C	L
NEUR1_dasN	DRYLKICYLSYGVWLKRKH	AYICLAVIW	19	C	L
NEUR1_equC	DRYLKICYLSYGVWLKRKH	AYICLAVIW	19	C	L
NEUR1_canF	DRYLKICYLSYGVWLKRKH	AYICLAVIW	19	C	L
NEUR1_susS	DRYLKICYLSYGVWLKRKH	AYICLAVIW	19	C	L
NEUR1_pteV	DRYLKICYLSYGVWLKRKH	AYICLAVIW	19	C	L
NEUR1_choH	DRYLKICYLSYGVWLKRKH	AYICLAVIW	19	C	L
NEUR1_musM	DRYLKICYLSYGVWLKRKH	AYICLAVIW	19	C	L
NEUR1_ratN	DRYLKICYLSYGVWLKRKH	AYICLAVIW	19	C	L
NEUR1_loxA	DRYLKICYLSYGVWLKRKH	AYICLAVIW	19	C	L
NEUR1_felC	DRYLKICYLSYGVWLKRKH	AYICLAVIW	19	C	L
NEUR1_turT	DRYLKICYLSYGVWLKRKH	AYICLAVIW	19	C	L
NEUR1_tupB	DRYLKICYLSYGVWLKRKH	AYICLAVIW	19	C	L
NEUR1_echT	DRYLKICYLSYGVWLKRKH	AYICLAVIW	19	C	L
NEUR1_dipO	DRYLKICYLSYGVWLKRKH	AYICLAVIW	19	C	L
NEUR1_bosT	DRYLKICYLSYGIWLKRKH	AYICLAVIW	19	C	L
NEUR1_eriE	DRYLKICYLSYGVWLKRKH	AYLCLAVIW	19	C	L
NEUR1_sorA	DRYLKICYLSYGVWLKRKH	AYICLVVIW	19	C	L
NEUR1_speT	DRYLKICYLSYGVWLKRKH	AFICLAVIW	19	C	L
NEUR1_oryC	DRYLKICYLSYGVWLKRRH	AYICLALIW	19	C	L
NEUR1_myoL	DRYLKICYLSYGVWLKRKH	TYICLAFIW	19	C	L
NEUR1_monD	DRYLKICHLSYGTWLKRHH	AFICLALIW	19	C	L
NEUR1_taeG	DRYLKICHLSYGTWLKRHH	AFICLAIIW	19	C	L
NEUR1_galG	DRYLKICHLAYGTWLKRHH	AFICLALIW	19	C	L
NEUR1_ornA	DRYLKICHLSYGTWLKRHH	AYICLAIIW	19	C	L
NEUR1_macE	DRYLKICHLSYGTWLKRHH	AYICLVIIW	19	C	L
NEUR1_gasA	DRYLKICHLRYGTWLKRHH	AFVCLALVW	19	C	L
NEUR1_anoC	DRYFKICHLSYGTWLKRHH	VFICLGIIW	19	C	L
NEUR1_tetN	DRYLKICHLRYGAWLKRHH	AFLCLASVW	19	C	L
NEUR1_xenT	DRYLKICHLRYGTWLKRRH	AFIALAVIW	19	C	L
NEUR1_takR	DRYLKICHLRYGTWFKRHH	AFLCLVFTW	19	C	L
NEUR1_oryL	DRYLKICHLRYGTWLKRQH	AFLCLVFVW	19	C	L
NEUR1_pimP	DRYLKICHLRYGTWLKRQH	IFLCLVFVW	19	C	L
NEUR1_danR	DRYLKICHLRYGTWLKRHH	AFLSVVFIW	19	C	L
NEUR1_calM	DRYLKICHLQYGSWLQRRH	VFMSLAFIW	19	C	L
NEUR2_galG	VCCLKICFPAYGNRFRRKH	GQILIACAW	19	C	P
NEUR2_anoC	VCCLKICFPVYGNRFRPGH	GWILIACAW	19	C	P
NEUR2_oncM	VCFVKVCYPLYGNRFNAVH	GRLLIACAW	19	C	P
NEUR2_xenT	VCCLKVCYPAYGNKFSTAH	SRILLLGIW	19	C	P
NEUR2_danR	VCCLKVCFPNYGNKFSSSH	ACVMVIGVW	19	C	P
NEUR2_pimP	VCCLKVCCPNYGNKFSSNH	ACVMVIGVW	19	C	P
NEUR2_tetN	VCCLKVCLPNLGSKFSSSH	ARLLVAGVW	19	C	P
NEUR2_takR	VCCLKVCFPNHGSRFSSSH	ARLLVVGVW	19	C	P
NEUR2_gasA	VCCLKVCFPNHGNRFSSSH	ARLLVVAVW	19	C	P
NEUR2_oryL	VCCLKVCFPNHGNKFSFSH	ARLLVAGVW	19	C	P
NEUR3_galGal    IRFLVTNSSKSNSNKISKNT    VHILITFIW       20      N       S
NEUR3_taeGut    IRFLVTNSPKSNsNKITKNT    VCILIAFIW       20      F       P 
NEUR3_anoCar    IRFLVTFSSKPAGHKINRKV    MHICIMLIW       20      S       S
NEUR3_xenTro    IRYRVTSSFKYSGCTIEKKA    VCILIMCIW       20      G       F
NEUR3a_danRe    VRYLVTGNPPKSGSKFRRKT    ISILIGVIW       20      G       P
NEUR3a_tetNi    IRYLVTGSPPRSGVQFQKKT    ICVVICAIW       20      G       P
NEUR3a_takRu    IRFLVTGTPPRSGIKFQKKT    ISVVISAIW       20      G       P
NEUR3a_gasAc    VRYLVTGNPPRSGLRLQRKT    VSMVIGAVW       20      G       P
NEUR3_calMil    VRFLVTSTTQN.........    .........       20      S       T
NEUR3_petMar    VRYKGTSTQVHsVKQITKRA    MLAVIVAVW       20      S       Q
NEUR3b_danRe    VRFIVSLTLQSPKEKISKRN    AKILVATTW       20      L       L
NEUR3b_tetNi    VRFTVSLNLQSPEEKISWKS    VKIMCLLIW       20      L       L
NEUR3b_takRu    VRFTVSLNLQSPeEKITWKS    VKIMCMWVW       20      L       L
NEUR3b_gasAc    VRFIVSLNLQSPNEKISWRK    VKLLCACTW       20      L       L
NEUR3b_oryLa    VRFIVSLNLHSPKEKVSWRK    VKILCLWSW       20      L       L
NEUR4_ornAna    TRYIKGCHPHRGHFINTAN     ISVALILIW       19      C       P
NEUR4_galGal    TRYIKGCHPERAHCISNSS     MTVAMVLIW       19      C       P
NEUR4_taeGut    TRYIKGCHPERGHCISNSS     MSVALVLIW       19      C       P
NEUR4_anocar    TRYIKGCHPDRGKCISNSS     ISVALFLIW       19      C       P
NEUR4_xenTro    TRYIKGCHPQRANCISNGS     ITISLALIW       19      C       P
NEUR4_danRer    TRFIKGCHPHKAHCITNST     VAVCVVFIW       19      C       P
NEUR4_tetNig    TRYIKGCQPSRAALISRSS     VSVCLLLIW       19      C       P
NEUR4_gasAcu    TRYIKGCHPNKAYCISTNT     IAVSLICIW       19      C       P
NEUR4_calMil    ...........AVSISAGS     IAASLVLIW       19      .       .
NEUR4_petMar    ...........PTKVTSTS     MVVSLALVW       19      .       .
TMT_monDom	ERYRTL-TLCPGQGADYQK	ALLAVAGSW	19	-	L
TMT_macEug	ERYRTL-TLCPRQGTDYHK	ALLAVAGSW	19	-	L
TMT_ornAna	ERYRTL-TLHPKQSTDYQK	AVLAVGASW	19	-	L
TMT_galGal	ERYSTL-TLCNKRSDDYRK	ALLAVGGSW	19	-	L
TMT_taeGut	ERYNTL-TLCHKRSDDFRK	ALLAVAGSW	19	-	L
TMT_anoCar	ERYSTL-TQTNKRGSDYQK	ALLGVGGSW	19	-	Q
TMT_xenTro	ERYSTL-TLYNKGGPNFKK	ALLAVASSW	19	-	L
TMT_danRer	ERYCTMMGSTEADATNYKK	VIGGVLMSW	19	M	S
TMT_pimPro	ERYCTMMGATQADSTNYKK	VAMGIAFSW	19	M	A
TMTa_takRu	ERYSTMMTPTEADPSNYCK	VCLGITLSW	19	M	P
TMT_tetNig	ERYSTMMTPTEADSSNYCK	VCLGIGLSW	19	M	P
TMT_gasAcu	ERYSTMVAPTEADSSNYHK	ISLGITLSW	19	V	P
TMT_oryLat	ERYSTMMTPAEADSSNYRK	ISLGIILSW	19	M	P
TMTb_takRu	ERYCTMVSSTIASNRDYRP	VLGGICFSW	19	V	S
TMTa_calMi	DRYITITGTTEADITNYNK	TIVGIALSW	19	T	T
TMT1_plaDu	ERYLAVVRPFDVGNLTNRR	VIAGGVFVW	19	V	P
TMT2_anoGa	ERYCLISRPFSSRNLTRRG	AFLAIFFIW	19	S	P
TMT_triCas	ERYLLIARPFRNNALNFHS	AALSVFSIW	19	A	P
TMT_bomMor	ERYLMVTRPLTSRHLSSKG	AVLSIMFIW	19	T	P
ENCEPH_hom	ERYIRVVHARVINFSW	AWRAITYIW	16	V	A
TMT_aedAe	ERFCLISHPFSSRSLSRRG	AVFAILFIW	19	S	P
TMT_culPi	ERFYLISRPFSSRSLSRRG	ALGAVLLIW	19	S	P
ENCEPH_lox	ERYIRVVHARVINFSW	AWRAITYIW	16	V	A
TMT1_anoGa	ERFCLISRPFAAQNRSKQG	ACLAVLFIW	19	S	P
ENCEPH_can	ERYIRVVHARVINFSW	AWRAITYIW	16	V	A
TMT_triCa	ERYLLIARPFRNNALNFHS	AALSVFSIW	19	A	P
ENCEPH_oto	ERYIRVVHARVINFSW	AWRAITYIW	16	V	A
ENCEPH_mus	ERYIRVVHARVINFSW	AWRAITYIW	16	V	A
ENCEPH_ano	ERYIRVVHARVIDFSW	SWRAITYIW	16	V	A
ENCEPH_gal	ERYIRVVHAKVIDFSW	SWRAITYIW	16	V	A
ENCEPH_mon	ERYNRIVHAKVINFSW	AWRAITYIW	16	V	A
ENCEPH_pte	ERYIRVVQARAIDFSW	AWRTITYIW	16	V	A
ENCEPH_squ	ERYIRVVNATAIDFSW	AWRAITYIW	16	V	A
ENCEPH_xen	ERYARVVYGKYVNSSW	SKRSITFVW	16	V	G
ENCEPH_dan	ERYIRVVHAKVVDFPW	AWRAITHIW	16	V	A
ENCEPH_tak	ERYIRVVHAQVVDFPW	AWRAIGHIW	16	V	A
ENCEPH_gas	ERYIRVVHAQVVDFPW	AWRAIGHIW	16	V	A
ENCEPH_ory	ERYIRVVHAQVVDFPW	AWRAIGHIW	16	V	A
ENCEPH_cal	ERYIRVVNAKATNFPW	AWRAITYTW	16	V	A
ENCEPH_squ	ERYIRVVNATAIDFSW	AWRAITYIW	16	V	A
ENCEPH_pet	ERYARLIKAQVLDFSW	AWRAVTYTW	16	I	A
RGR_homSap	GRYHHYCTRSQLAWNS	AVSLVLFVW	16	C	R
RGR_panTro	GRYHHYCTRSQLAWNS	AISLVLFVW	16	C	R
RGR_gorGor	GRYHHYCTGSTLACKS	AVSLVLSGR	16	C	G
RGR_macMul	GRYHHYCTRSQLAWNS	AISLVLFVW	16	C	R
RGR_ponPyg	GRYHHYCTGSQLAWNS	AISLVLFVW	16	C	G
RGR_calJac	GRYHHYCTGSQLAWNS	AISLVLFVW	16	C	G
RGR_nomLeu	GRYHHYCTGSQLAWNS	AISLVLFVW	16	C	G
RGR_tarSyr	GRYHHYCTGSQLAWNT	AISLVLFVW	16	C	G
RGR_pteVam	GRYHHYCTGSRLAWNT	AVSLVLFVW	16	C	G
RGR_oryCun	GRYHHYCTGSQLAWNT	AVLLVLFVW	16	C	G
RGR_ochPri	GRYHHYCTGSQLAWNT	AVLLVLFVW	16	C	G
RGR_otoGar	GRYHHYCTGRPLAWST	AISLVLFVW	16	C	G
RGR_micMur	GRYHHYCTGSPLAWST	AISLVLFVW	16	C	G
RGR_musMus	GRYHHYCTGRQLAWDT	AIPLVLFVW	16	C	G
RGR_ratNor	GRYHHYCTGRQLAWDT	AIPLVLFVW	16	C	G
RGR_cavPor	GRHQQCCTRGRLTWST	AVPLVLFVW	16	C	R
RGR_speTri	GRYHHYCTGSQLAWNT	AIPLVLFVW	16	C	G
RGR_sorAra	GRYHHYCTGRQLAWDV	AIALVIFVW	16	C	G
RGR_myoLuc	GRYHHYCTGSRLAWRT	AASLVLFVW	16	C	G
RGR_canFam	GRYHHYCTRGQLAWNT	AISLVLCVW	16	C	R
RGR_felCat	GRYHHYCSGSQLAWNT	AISLVICVW	16	C	G
RGR_bosTau	GRYHHFCTGSRLDWNT	AVSLVFFVW	16	C	G
RGR_turTru	GRYHHYCTGSRLDWNT	AVSLVFFVW	16	C	G
RGR_susScr	GRYHHYCTRSRLDWNT	AVSLVFFVW	16	C	R
RGR_equCab	GRYHHYCTRSRLAWNT	AVFLVFFVW	16	C	R
RGR_eriEur	GRYHHHCTRSRLAWNT	AVFLVFFVW	16	C	R
RGR_dipOrd	GRCHHHCTGSLLGWDT	AVSLVIFVW	16	C	G
RGR_loxAfr	ERYHHYCTRSRLAWSS	ASALVLFVW	16	C	R
RGR_proCap	ERYHHYCTGSKLAWSS	AGALVLFMW	16	C	G
RGR_echTel	ERYHHYCTGSQFTWSS	ASTLVLFMW	16	C	G
RGR_dasNov	ERCHRHCIGRRLAWST	AGCLVLCLW	16	C	G
RGR_choHof	ERYRHHCTGSQLSWST	AGSLVLCVW	16	C	G
RGR_ornAna	DRYLRHCSRSKPQWGT	AVSTVLFAW	16	C	R
RGR_anoCar	DRHHQYCTGNKLQWGS	VIPMTIFLW	16	C	G
RGR_galGal	DRYHHYCTRSKLQWST	AISMMVFAW	16	C	R
RGR_taeGut	DRYHHYCTRSRLQWST	AVSMMVFAW	16	C	R
RGR_xenTro	DRYHQYCTRSKLHWST	AVSVVFFIW	16	C	R
RGR_xenLae	DRYHQYCTRSKLHWGT	AVSMVLFVW	16	C	R
RGR1_gasAc	DRYHQYCTRTKLQWSS	AITLAVFVW	16	C	R
RGR1_takRu	DRYHQYCTRTKLQWSS	AITLAVFIW	16	C	R
RGR1_tetNi	DRYHQYCTRTKLQWSS	AITLAVFIW	16	C	R
RGR1_pimPr	DRYHQYCTRTKLQWSS	AITLVIFIW	16	C	R
RGR1_osmMo	DRYHQYCTRTKLQWSS	AITLVMFIW	16	C	R
RGR1_gadMo	DRYHQYCTRTELQWSS	AVTLSVFIW	16	C	R
RGR1_danRe	DRYHQYCTRTKLQWSS	AITLVLFTW	16	C	R
RGR1_oryLa	DRYHQYCTRTKLQWST	AITLAVLVW	16	C	R
RGR_calMil	DRYHQNCSRSRLQWSS	AITVTVFIW	16	C	R
RGR2_gasAc	DRYHQYCTRQKLFWST	TLTMSAIIW	16	C	R
RGR2_tetNi	DRYHQYCTRQKLFWST	TLTMSSIIW	16	C	R
RGR2_oryLa	DRYHQYCTRQKLFWST	SITISLIIW	16	C	R
RGR2_danRe	DRYHQYCTKQKMFWST	SITISCLIW	16	C	K
RGR2_pimPr	DRYHLYCTKQKMFWST	SGTISALIW	16	C	K
RGR2_gadMo	DRYHQYCTRQKLFWST	TVTMCCIVW	16	C	R
RGR2_hipHi	DRYHQYCTRQKLFWST	TLTMSGIIW	16	C	R
RGR2_oncMy	DRYHQYVTNQKLFWST	AWTISIIIW	16	V	N
RGR2_esoLu	DRYHQYVTNQKLFWST	AWTFSIIIW	16	V	N
RGR2_poeRe	DRYHQYCTRQKLFWST	TLTMSGIIW	16	C	R
MEL1_homSa	DRYLVITRPLATFGVASKRR	AAFVLLGVW	20	T	P
MEL1_panTr	DRYLVITRPLATFGVASKRR	AAFVLLGVW	20	T	P
MEL1_gorGo	DRYLVITRPLATFGVASKRR	AAFVLLGVW	20	T	P
MEL1_ponAb	DRYLVITRPLATIGVASKRR	AAFVLLGVW	20	T	P
MEL1_rheMa	DRYLVITRPLATIGVASKRR	AAFVLLGVW	20	T	P
MEL1_calJa	DRYLVITRPLATIGVASTKR	AAFVLLGVW	20	T	P
MEL1_micMu	DRYLVITRPLASVGTASKRR	AGLVLLGVW	20	T	P
MEL1_otoGa	DRYLVITRPLTTVGVASKRR	AALVLLGVW	20	T	P
MEL1_musMu	DRYLVITRPLATIGRGSKRR	TALVLLGVW	20	T	P
MEL1_ratNo	DRYLVITRPLATIGMRSKRR	TALVLLGVW	20	T	P
MEL1_nanEh	DRYLVITRPLATIGVASKRR	TALVLLGVW	20	T	P
MEL1_phoSu	DRYLVITRPLATIGMGSKRR	TALVLLGIW	20	T	P
MEL1_dipOr	DRYLVITRPLATIGVTSKRR	TAFVLLGVW	20	T	P
MEL1_cavPo	DRYLVITRPLATIGVASKRQ	AALVLLGVW	20	T	P
MEL1_speTr	DRYLVITRPLATIGMASKKR	AAFFLLGVW	20	T	P
MEL1_oryCu	DRYLVITRPLAAVGMVSKKR	AGLVLLGVW	20	T	P
MEL1_ochPr	DRYLVITRPLAAVGMVSKRR	TGLVLLGVW	20	T	P
MEL1_bosTa	DRYLVITRPLATVGMVSKRR	AALVLLGVW	20	T	P
MEL1_turTr	DRYLVITRPLATVGMVSKRR	AALVLLGVW	20	T	P
MEL1_susSc	DRYLVITHPLATVGMVSKRR	AALVLLGVW	20	T	P
MEL1_equCa	DRYLVITRPLATVGVVSKRW	AALVLLGIW	20	T	P
MEL1_felCa	DRYLVITHPLATIGVVSKRR	AALVLLGVW	20	T	P
MEL1_canFa	DRYLVITHPLAAVGVVSKRR	AALVLLGVW	20	T	P
MEL1_myoLu	DRYLVITRPLA-IGVVSKRR	AALVLLGVW	20	T	P
MEL1_pteVa	DRYLVITRPLAAIGVVSKRR	AALVLLGVW	20	T	P
MEL1_eriEu	DRYLVITRPLATIGVVSKRR	VALVLLGVW	20	T	P
MEL1_loxAf	DRYLVITRPLATIGVVSKRR	AALVLLGIW	20	T	P
MEL1_proCa	DRYLVITRPLATIGVVSKRR	TALVLLGTW	20	T	P
MEL1_echTe	DRYLVITRPLATIGVVSKRR	AALVLLVIW	20	T	P
MEL1_smiCr	DRYFVITRPLASIGMISKKK	TGLILLGVW	20	T	P
MEL1_monDo	DRYFVITRPLASIGVISKKK	TGFILLGVW	20	T	P
MEL1_ornAn	DRYFVITRPLASIGVISKKR	ALLILTGVW	20	T	P
MEL1_anoCa	DRYFVITRPLASIGAMSTKK	ALLILSGVW	20	T	P
MEL1_taeGu	DRYFVITKPLASVGVTSKKK	ALIILVGVW	20	T	P
MEL1_galGa	DRYFVITKPLASVRVMSKKK	ALIILVGVW	20	T	P
MEL1_xenTr	DRYFVITRPLTSIGVMSKKR	AVLILSGVW	20	T	P
MEL1_danRe	DRYFVITRPLASIGVLSQKR	ALLILLVAW	20	T	P
MEL1_danRe	DRYFVITRPLASIGVMSRKR	ALLILSAAW	20	T	P
MEL1_takRu	DRYFVITRPLTSIGVLSRKR	AFVILMTVW	20	T	P
MEL1_gasAc	DRYFVITRPLTSIGMMSRRR	ALLILMGAW	20	T	P
MEL1_oryLa	DRYFVITRPLTSIGVLSRKR	ALLILSAAW	20	T	P
MEL1_calMi	DRYFVITRPLASIGVLSHRR	AGLIILSLW	20	T	P
MEL1_petMa	DRYLVLTRPLASIGAMSKRR	AMYITAAVW	20	T	P
MEL2_galGa	DRYLVITKPLRSIQWTSKKR	TIQIIAAVW	20	T	P
MEL2_anoCa	DRYCVITKPLQSIKRTSKKR	TCIIIVFVW	20	T	P
MEL2_xenLa	NRYIVITKPLQSIQWSSKKR	TSQIIVLVW	20	T	P
MEL2_danRe	DRYLVITKPLQTIQWNSKRR	TGLAILCIW	20	T	P
MEL2_tetNi	DRYVVITKPLQTIRRSSKRR	TALAILMVW	20	T	P
MEL2_gasAc	DRYLVITKPLQAIHWGSKRR	TTLAILLVW	20	T	P
MEL1_plaDu	DRFYVITNPLGAAQTMTKKR	AFIILTIIW	20	T	P
MEL1_capCa	DRYMVIAKPFYAMKHVSHKR	SLIQIILAW	20	A	P
MEL1_helRo	DRYLVVGQPLAMLNQSHFRR	SFYHVLIIW	20	G	P
MEL1_todPa	DRYNVIGRPMAASKKMSHRR	AFIMIIFVW	20	G	P
TMT_triCys	ERFITIVLPLKRDTILSTKN	IYIGLGILW	20	V	P

Reference collection of structurally determined GPCR

>RHO1_bosTau cow rod rhodopsin
MNGTEGPNFYVPFSNKTGVVRSPFEAPQYYLAEPWQFSMLAAYMFLLIMLGFPINFLTLYVTVQHKKLRTPLNYILLNLAVADLFMVFGGFTTTLYTSLHGYFVFGPTGCNLEGFFATLGGEIALWSLVVLAI
ERYVVVCKPMSNFRFGENHAIMGVAFTWVMALACAAPPLVGWSRYIPEGMQCSCGIDYYTPHEETNNESFVIYMFVVHFIIPLIVIFFCYGQLVFTVKEAAAQQQESATTQKAEKEVTRMVIIMVIAFLICWL
PYAGVAFYIFTHQGSDFGPIFMTIPAFFAKTSAVYNPVIYIMMNKQFRNCMVTTLCCGKNPLGDDEASTTVSKTETSQVAPA*

>MEL1_todPac Todarodes pacificus (squid) Gq X70498 480 11106382 Mollusca 'squid rhodopsin' 3D: May 2008 Cys 337 palmitoyled
MGRDLRDNETWWYNPSIVVHPHWREFDQVPDAVYYSLGIFIGICGIIGCGGNGIVIYLFTKTKSLQTPANMFIINLAFSDFTFSLVNGFPLMTISCFLKKWIFGFAACKVYGFIGGIFGFMSIMTMAMISI
DRYNVIGRPMAASKKMSHRRAFIMIIFVWLWSVLWAIGPIFGWGAYTLEGVLCNCSFDYISRDSTTRSNILCMFILGFFGPILIIFFCYFNIVMSVSNHEKEMAAMAKRLNAKELRKAQAGANAEMRLAKI
SIVIVSQFLLSWSPYAVVALLAQFGPLEWVTPYAAQLPVMFAKASAIHNPMIYSVSHPKFREAISQTFPWVLTCCQFDDKETEDDKDAETEIPAGESSDAAPSADAAQMKEMMAMMQKMQQQQAAYPPQGY
APPPQGYPPQGYPPQGYPPQGYPPQGYPPPPQGAPPQGAPPAAPPQGVDNQAYQA*

>ADRB1_melGal turkey Beta 1 adrenergic receptor with stabilising mutations And bound cyanopindolol
MGAELLSQQWEAGMSLLMALVVLLIVAGNVLVIAAIGSTQRLQTLTNLFITSLACADLVVGLLVVPFGATLVVRGTWLWGSFLCELWTSLDVLCVTASIETLCVIAI
DRYLAITSPFRYQSLMTRARAKVIICTVWAISALVSFLPIMMHWWRDEDPQALKCYQDPGCCDFVTNRAYAIASSIISFYIPLLIMIFVALRVYREA
KEQIRKIDRASKRKRVMLMREHKALKTLGIIMGVFTLCWLPFFLVNIVNVFNRDLVPDWLFVAFNWLGYANSAMNPIIYCRSPDFRKAFKRLLAFPRKADRRLHHHHHH*

>ADRB2_homSap beta 2 adrenergic receptor 365 aa  
MGQPGNGSAFLLAPNRSHAPDHDVTQQRDEVWVVGMGIVMSLIVLAIVFGNVLVITAIAKFERLQTVTNYFITSLACADLVMGLAVVPFGAAHILMKMWTFGNFWCEFWTSIDVLCVTASIETLCVIAV
DRYFAITSPFKYQSLLTKNKARVIILMVWIVSGLTSFLPIQMHWYRATHQEAINCYANETCCDFFTNQAYAIASSIVSFYVPLVIMVFVYSRVFQEAKRQLQKIDKSEGRFHVQNLSQVEQDGRTGHGL
RRSSKFCLKEHKALKTLGIIMGTFTLCWLPFFIVNIVHVIQDNLIRKEVYILLNWIGYVNSGFNPLIYCRSPDFRIAFQELLCLRRSSLKAYGNGYSSNGNTGEQSG*

>ADORA2A_homSap adenosine adrenergic receptor 2A
MPIMGSSVYITVELAIAVLAILGNVLVCWAVWLNSNLQNVTNYFVVSLAAADIAVGVLAIPFAITISTGFCAACHGCLFIACFVLVLTQSSIFSLLAIAI
DRYIAIRIPLRYNGLVTGTRAKGIIAICWVLSFAIGLTPMLGWNNCGQPKEGKNHSQGCGEGQVACLFEDVVPMNYMVYFNFFACVLVPLLLMLGVYLRI
FLAARRQLKQMESQPLPGERARSTLQKEVHAAKSLAIIVGLFALCWLPLHIINCFTFFCPDCSHAPLWLMYLAIVLSHTNSVVNPFIYAYRIREFRQTFR
KIIRSHVLRQQEPFKAAGTSARVLAAHGSDGEQVSLRLNGHPPGVWANGSAPHPERRPNGYALGLVSGGSAQESQGNTGLPDVELLSHELKGVCPEPPGLDDPLAQDGAGVS*

The C2 loop is highly conserved within each orthology class for GPCR with determined structure:

        RHO1 in vertebrates                  MEL1 in vertebrates                    ADRB1 in vertebrates                   ADRB2 orthologs in tetrapods           ADORA2A in teleosts
homSap  ERYVVVCKPMSNFRFGENHAIMGVAFTW  homSa  DRYLVITRPLATFGVASKRRAAFVLLGVW  homSap  DRYLAITSPFRYQSLLTRARARGLVCTVW  homSap  DRYFAITSPFKYQSLLTKNKARVIILMVW  homSap  DRYIAIRIPLRYNGLVTG TRAKGIIAICW
panTro  ERYVVVCKPMSNFRFGENHAIMGVAFTW  panTr  DRYLVITRPLATFGVASKRRAAFVLLGVW  panTro  DRYLAITSPFRYQSLLTRARARGLVCTVW  panTro  DRYFAITSPFKYQSLLTKNKARVIILMVW  panTro  DRYIAIRIPLRYNGLVTGTRAKGIIAICW
gorGor  ERYVVVCKPMSNFRFGENHAIMGVAFTW  gorGo  DRYLVITRPLATFGVASKRRAAFVLLGVW  ponAbe  DRYLAITSPFRYQSLLTRARARGLVCTVW  gorGor  DRYFAITSPFKYQSLLTKNKARVIILMVW  gorGor  DRYIAIRIPLRYNGLVTGTRAKGIIAICW
ponAbe  ERYVVVCKPMSNFRFGENHAIMGVAFTW  ponAb  DRYLVITRPLATIGVASKRRAAFVLLGVW  rheMac  DRYLAITSPFRYQSLLTRARARGLVCTVW  ponAbe  DRYFAITSPFKYQSLLTKNKARVIILMVW  ponAbe  DRYIAIRIPLRYNGLVTGTRAKGIIAICW
rheMac  ERYVVVCKPMSNFRFGENHAIMGVAFTW  rheMa  DRYLVITRPLATIGVASKRRAAFVLLGVW  calJac  DRYLAITSPFRYQSLLTRARARGLVCTVW  rheMac  DRYFAITSPFKYQSLLTKNKARVIILMVW  rheMac  DRYIAIRIPLRYNGLVTGTRAKGIIAICW
calJac  ERYVVVCKPMSNFRFGENHAIMGVAFTW  calJa  DRYLVITRPLATIGVASTKRAAFVLLGVW  micMur  DRYLAITSPFRYQSLLTRARARALVCTVW  calJac  DRYFAITSPFKYQSLLTKNKARVIILMVW  calJac  DRYIAIRIPLRYNGLVTGTRAKGIIAICW
micMur  ERYVVVCKPMSNFRFGENHAIMGVVFTW  micMu  DRYLVITRPLASVGTASKRRAGLVLLGVW  otoGar  DRYLAITSPFRYQSLLTRARARPLVCTVW  micMur  DRYFAITSPFKYQSLLTKNKARVVILMVW  micMur  DRYIAIRIPLRYNGLVTGTRAKGIIAICW
musMus  ERYVVVCKPMSNFRFGENHAIMGVVFTW  otoGa  DRYLVITRPLTTVGVASKRRAALVLLGVW  musMus  DRYLAITSPFRYQSLLTRARARALVCTVW  otoGar  DRYFAITSPFKYQSLLTKNKARVVILMVW  musMus  DRYIAIRIPLRYNGLVTGMRAKGIIAICW
ratNor  ERYVVVCKPMSNFRFGENHAIMGVAFTW  musMu  DRYLVITRPLATIGRGSKRRTALVLLGVW  ratNor  DRYLAITSPFRYQSLLTRARARALVCTVW  tupBel  DRYFAITSPFKYQSLLTKNKARVVILMVW  ratNor  DRYIAIRIPLRYNGLVTGVRAKGIIAICW
cavPor  ERYVVVCKPMSNFRFGENHAIMGVVFTW  ratNo  DRYLVITRPLATIGMRSKRRTALVLLGVW  cavPor  DRYLAITSPFRYQSLLTRARARVLVCTVW  dipOrd  DRYFAITSPFKYQSLLTKNKARVVILMVW  dipOrd  DRYIAIRIPLRYNSLVTCTRAKGIIAICW
speTri  ERYMVVCKPMSNFRFGENHAIMGVIFTW  dipOr  DRYLVITRPLATIGVTSKRRTAFVLLGVW  oryCun  DRYLAITSPFRYQSLLTRARARALVCTVW  cavPor  DRYFAITSPFKYQSLLTKNKARVVILMVW  cavPor  DRYIAIRIPLRYNGLVTCTRAKGIIAICW
oryCun  ERYVVVCKPMSNFRFGENHAIMGVAFTW  cavPo  DRYLVITRPLATIGVASKRQAALVLLGVW  ochPri  DRYLAITSPFRYQSLLTRARARALVCTVW  oryCun  DRYFAITSPFKYQSLLTKNKARVVILMVW  speTri  DRYIAIRIPLRYNGLVTGMRAKGIIAICW
ochPri  ERYVVVCKPMSNFRFGENHAIMGVAFTW  speTr  DRYLVITRPLATIGMASKKRAAFFLLGVW  bosTau  DRYLAITSPFRYQSLLTRARARALVCTVW  ochPri  DRYFAITSPFKYQSLLTKNKARVVVLMVW  oryCun  DRYIAIRIPLRYNGLVTGTRAKGIIAICW
bosTau  ERYVVVCKPMSNFRFGENHAIMGVAFTW  oryCu  DRYLVITRPLAAVGMVSKKRAGLVLLGVW  equCab  DRYLAITSPFRYQSLLTRARARALVCTVW  equCab  DRYFAITSPFKYQSLLTKNKARVVILMVW  ochPri  DRYIAIRIPLRYNGLVTGSRAKGIIAICW
equCab  ERYVVVCKPMSNFRFGENHAIMGVAFTW  ochPr  DRYLVITRPLAAVGMVSKRRTGLVLLGVW  felCat  DRYLAITSPFRYQSLLTRARARALVCTVW  felCat  DRYFAITSPFKYQSLLTKNKARVVILMVW  turTru  DRYIAIRIPLRYNGLVTGTRAKGIIAVCW
felCat  ERYVVVCKPMSNFRFGENHAIMGVAFTW  bosTa  DRYLVITRPLATVGMVSKRRAALVLLGVW  canFam  DRYLAITAPFRYQSLLTRARARALVCTVW  canFam  DRYFAITSPFKYQSLLTKNKARVVILMVW  bosTau  DRYIAIRIPLRYNGLVTGTRAKGIIAVCW
canFam  ERYVVVCKPMSNFRFGENHAIMGVAFTW  turTr  DRYLVITRPLATVGMVSKRRAALVLLGVW  myoLuc  DRYLAITSPFRYQSLLTRARARALVCTVW  myoLuc  DRYFAITSPFKYQSLLTKNKARVVILLVW  canFam  DRYIAIRIPLRYNGLVTGTRAKGIIAVCW
myoLuc  ERYVVVCKPMSNFRFGENHAIMGLAFTW  equCa  DRYLVITRPLATVGVVSKRWAALVLLGIW  pteVam  DRYLAITSPFRYQSLLTRARARALVCTVW  pteVam  DRYFAITSPFKYQSLLTKNKARVVILMVW  myoLuc  DRYIAIRIPLRYNGLVTGARAKGIIAICW
pteVam  ERYVVVCKPMSNFRFGENHAIMGLALTW  felCa  DRYLVITHPLATIGVVSKRRAALVLLGVW  echTel  DRYLAITSPFRYQSLLTRARARVLVCTVW  eriEur  DRYFAITSPFKYQSLLTKNKARVVILMVW  eriEur  DRYIAIRIPLRYNGLVTGQRAKGIIAVCW
eriEur  ERYVVVCKPMSNFRFGENHAIMGVAFTW  canFa  DRYLVITHPLAAVGVVSKRRAALVLLGVW  choHof  DRYLAITSPFRYQSLLTRARARALVCTVW  sorAra  DRYFAITSPFKYQSLLTKNKARGVILMVW  loxAfr  DRYIAIRIPLRYNGLVTGTRAKGIIAVCW
dasNov  ERYVVVCKPMSNFRFGENHAVMGVAFTW  myoLu  DRYLVITRPLA-IGVVSKRRAALVLLGVW  monDom  DRYIAITSPFRYQSLLTRARARALVCTVW  proCap  DRYFAITSPFKYQSLLTKNKARVVILMVW  proCap  DRYIAIRIPLRYNGLVTGTRAKGIIAVCW
monDom  ERYVVVCKPMSNFRFGENHAIIGVAFTW  pteVa  DRYLVITRPLAAIGVVSKRRAALVLLGVW  ornAna  DRYIAITSPFRYRSLLTRARARGLVCGVW  echTel  DRYFAITSPFKYQSLLTKNKARVVILMVW  galGal  DRIIAIRIPLRYNGLVTGSRAKGIIAICW
ornAna  ERYIVVCKPMSNFRFGENHAIMGVAFTW  eriEu  DRYLVITRPLATIGVVSKRRVALVLLGVW  galGal  DRYLAITSPFRYQSLMTRARAKGIICTVW  dasNov  DRYFAITSPFKYQSLLTKNKARVVILMVW  taeGut  DRIIAIRIPLRYNGLVTGSRAKGIIAICW
galGal  ERYVVVCKPMSNFRFGENHAIMGVAFSW  loxAf  DRYLVITRPLATIGVVSKRRAALVLLGIW  taeGut  DRYLAITSPFRYQSLMTKGRAKGIICTVW  monDom  DRYFAITAPFRYQSMLTKGKARVVILVVW  xenTro  DRYIAIRIPLRYNSLVTSRRANAIIAVCW
taeGut  ERYVVVCKPMSNFRFGENHAIMGVAFSW  proCa  DRYLVITRPLATIGVVSKRRTALVLLGTW  anoCar  DRYLAITSPFRYQSLMTKKRAKIIVCVVW  galGal  DRYFAITSPFKYQSLLTKSKARVVILVVW  tetNig  DRYIAIKLPLRYNGLVTGQRAQAIIAICW
anoCar  ERYVVICKPMSNFRFGETHALIGVSCTW  echTe  DRYLVITRPLATIGVVSKRRAALVLLVIW  xenTro  DRYIAITSPLKYEMLVTKVRARLTVCLVW  taeGut  DRYFAITSPFKYQSLLTKGKARVVILVVW  fugRub  DRYIAIKLPLRYNSLVTGKRAQGIIAICW
xenTro  ERYVVVCKPMANFRFGENHAIMGVVFTW  monDo  DRYFVITRPLASIGVISKKKTGFILLGVW  tetNig  DRYVAITSPFRYQSLLTKARARAMVCAVW  anoCar  DRYFAITSPFKYQSHLTKNKARVIILLVW  gasAcu  DRYIAIKIPLRYNGLVTGQRAQGIIAICW
tetNig  ERYIVVCKPVTNFRFGEKHAIAGLAFTW  ornAn  DRYFVITRPLASIGVISKKRALLILTGVW  fugRub  DRYVAITSPFRYQSLLTKARAKAMVCAVW  xenTro  DRYFAITSPFRYQSLLTKCKARIVILLVW  oryLat  DRYIAIKIPLRYNSLVTSQRARGIIAICW
fugRub  ERYIVVCKPMTNFRFGEKHAIAGLVFTW  anoCa  DRYFVITRPLASIGAMSTKKALLILSGVW  gasAcu  DRYVAITSPFRYQSLLTKARARTVVCVVW                                         danRer  DRYIAIKIPLRYNSLVTGQRARGIIAICW
gasAcu  ERYVVVCKPMSNFRFGEKHAIAGLLFTW  galGa  DRYFVITKPLASVRVMSKKKALIILVGVW  oryLat  DRYVAITSPFRYQSLLTKSRAKAVVCVVW    
oryLat  ERYVVVCKPMTNFRFEEKHAIAGLAFSW  xenTr  DRYFVITRPLTSIGVMSKKRAVLILSGVW  danRer  DRYIAIISPFRYQSLLTKARAKVVVCAVW    
danRer  ERWMVVCKPVSNFRFGENHAIMGVAFTW  danRe  DRYFVITRPLASIGVLSQKRALLILLVAW  petMar  DRYIAVARPLRYETLMNKRRARFIIVAVW    
petMar  ERYIVICKPMGNFRFGSTHAYMGVAFTW  takRu  DRYFVITRPLTSIGVLSRKRAFVILMTVW      
                                      gasAc  DRYFVITRPLTSIGMMSRRRALLILMGAW      
                                      oryLa  DRYFVITRPLTSIGVLSRKRALLILSAAW      
                                      calMi  DRYFVITRPLASIGVLSHRRAGLIILSLW      
                                      petMa  DRYLVLTRPLASIGAMSKRRAMYITAAVW

See also: Curated Sequences | Ancestral Introns | Informative Indels | Ancestral Sequences | Alignment | Update Blog

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