AGRA2_DANRE
ID AGRA2_DANRE Reviewed; 1367 AA.
AC E7FBY6;
DT 13-APR-2016, integrated into UniProtKB/Swiss-Prot.
DT 20-JAN-2016, sequence version 2.
DT 03-AUG-2022, entry version 76.
DE RecName: Full=Adhesion G protein-coupled receptor A2 {ECO:0000303|PubMed:27979830};
DE AltName: Full=G-protein coupled receptor 124 {ECO:0000303|PubMed:27979830};
DE Flags: Precursor;
GN Name=adgra2 {ECO:0000303|PubMed:27979830,
GN ECO:0000312|ZFIN:ZDB-GENE-081104-363};
GN Synonyms=gpr124 {ECO:0000303|PubMed:26051822, ECO:0000303|PubMed:27979830};
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Tuebingen;
RX PubMed=23594743; DOI=10.1038/nature12111;
RA Howe K., Clark M.D., Torroja C.F., Torrance J., Berthelot C., Muffato M.,
RA Collins J.E., Humphray S., McLaren K., Matthews L., McLaren S., Sealy I.,
RA Caccamo M., Churcher C., Scott C., Barrett J.C., Koch R., Rauch G.J.,
RA White S., Chow W., Kilian B., Quintais L.T., Guerra-Assuncao J.A., Zhou Y.,
RA Gu Y., Yen J., Vogel J.H., Eyre T., Redmond S., Banerjee R., Chi J., Fu B.,
RA Langley E., Maguire S.F., Laird G.K., Lloyd D., Kenyon E., Donaldson S.,
RA Sehra H., Almeida-King J., Loveland J., Trevanion S., Jones M., Quail M.,
RA Willey D., Hunt A., Burton J., Sims S., McLay K., Plumb B., Davis J.,
RA Clee C., Oliver K., Clark R., Riddle C., Elliot D., Threadgold G.,
RA Harden G., Ware D., Begum S., Mortimore B., Kerry G., Heath P.,
RA Phillimore B., Tracey A., Corby N., Dunn M., Johnson C., Wood J., Clark S.,
RA Pelan S., Griffiths G., Smith M., Glithero R., Howden P., Barker N.,
RA Lloyd C., Stevens C., Harley J., Holt K., Panagiotidis G., Lovell J.,
RA Beasley H., Henderson C., Gordon D., Auger K., Wright D., Collins J.,
RA Raisen C., Dyer L., Leung K., Robertson L., Ambridge K., Leongamornlert D.,
RA McGuire S., Gilderthorp R., Griffiths C., Manthravadi D., Nichol S.,
RA Barker G., Whitehead S., Kay M., Brown J., Murnane C., Gray E.,
RA Humphries M., Sycamore N., Barker D., Saunders D., Wallis J., Babbage A.,
RA Hammond S., Mashreghi-Mohammadi M., Barr L., Martin S., Wray P.,
RA Ellington A., Matthews N., Ellwood M., Woodmansey R., Clark G., Cooper J.,
RA Tromans A., Grafham D., Skuce C., Pandian R., Andrews R., Harrison E.,
RA Kimberley A., Garnett J., Fosker N., Hall R., Garner P., Kelly D., Bird C.,
RA Palmer S., Gehring I., Berger A., Dooley C.M., Ersan-Urun Z., Eser C.,
RA Geiger H., Geisler M., Karotki L., Kirn A., Konantz J., Konantz M.,
RA Oberlander M., Rudolph-Geiger S., Teucke M., Lanz C., Raddatz G.,
RA Osoegawa K., Zhu B., Rapp A., Widaa S., Langford C., Yang F.,
RA Schuster S.C., Carter N.P., Harrow J., Ning Z., Herrero J., Searle S.M.,
RA Enright A., Geisler R., Plasterk R.H., Lee C., Westerfield M.,
RA de Jong P.J., Zon L.I., Postlethwait J.H., Nusslein-Volhard C.,
RA Hubbard T.J., Roest Crollius H., Rogers J., Stemple D.L.;
RT "The zebrafish reference genome sequence and its relationship to the human
RT genome.";
RL Nature 496:498-503(2013).
RN [2] {ECO:0000305}
RP FUNCTION, INTERACTION WITH RECK, AND SUBCELLULAR LOCATION.
RX PubMed=26051822; DOI=10.7554/elife.06489;
RA Vanhollebeke B., Stone O.A., Bostaille N., Cho C., Zhou Y., Maquet E.,
RA Gauquier A., Cabochette P., Fukuhara S., Mochizuki N., Nathans J.,
RA Stainier D.Y.;
RT "Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent
RT Wnt/beta-catenin pathway during brain angiogenesis.";
RL Elife 4:0-0(2015).
RN [3]
RP MUTAGENESIS OF 126-ASP--LEU-149, AND SUBCELLULAR LOCATION.
RX PubMed=27979830; DOI=10.1242/bio.021287;
RA Bostaille N., Gauquier A., Twyffels L., Vanhollebeke B.;
RT "Molecular insights into Adgra2/Gpr124 and Reck intracellular
RT trafficking.";
RL Biol. Open 5:1874-1881(2016).
RN [4]
RP MUTAGENESIS OF 126-ASP--LEU-149.
RX PubMed=27979884; DOI=10.1242/dev.146803;
RA Bostaille N., Gauquier A., Stainier D.Y., Raible D.W., Vanhollebeke B.;
RT "Defective adgra2 (gpr124) splicing and function in zebrafish ouchless
RT mutants.";
RL Development 144:8-11(2017).
RN [5]
RP FUNCTION.
RX PubMed=30026314; DOI=10.1126/science.aat1178;
RA Eubelen M., Bostaille N., Cabochette P., Gauquier A., Tebabi P.,
RA Dumitru A.C., Koehler M., Gut P., Alsteens D., Stainier D.Y.R.,
RA Garcia-Pino A., Vanhollebeke B.;
RT "A molecular mechanism for Wnt ligand-specific signaling.";
RL Science 361:0-0(2018).
CC -!- FUNCTION: Endothelial receptor which functions together with reck to
CC enable brain endothelial cells to selectively respond to Wnt7 signals
CC (wnt7a or wnt7b) (PubMed:26051822, PubMed:30026314). Plays a key role
CC in Wnt7-specific responses: Required for normal central nervous system
CC (CNS) vascularization where it functions cell-autonomously in the tip
CC cells of sprouting vessels (PubMed:26051822). Has a role in development
CC of dorsal root ganglia (PubMed:26051822). Acts as a Wnt7-specific
CC coactivator of canonical Wnt signaling: required to deliver reck-bound
CC Wnt7 to frizzled by assembling a higher-order RECK-ADGRA2-Fzd-LRP5-LRP6
CC complex (PubMed:30026314). Adgra2-tethering function does not rely on
CC its G-protein coupled receptor (GPCR) structure but instead on its
CC combined capacity to interact with RECK extracellularly and recruit the
CC Dishevelled scaffolding protein intracellularly (PubMed:30026314).
CC {ECO:0000269|PubMed:26051822, ECO:0000269|PubMed:30026314}.
CC -!- SUBUNIT: Interacts with reck. {ECO:0000269|PubMed:26051822}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:26051822,
CC ECO:0000269|PubMed:27979830}; Multi-pass membrane protein
CC {ECO:0000255}. Note=Colocalizes with reck at the plasma membrane.
CC {ECO:0000269|PubMed:26051822}.
CC -!- DOMAIN: The leucine-rich repeats (LRRs) are important for potentiation
CC of Wnt7 signaling. {ECO:0000250|UniProtKB:Q91ZV8}.
CC -!- PTM: Proteolytically cleaved into two subunits, an extracellular
CC subunit and a seven-transmembrane subunit.
CC {ECO:0000250|UniProtKB:Q96PE1}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 2 family.
CC Adhesion G-protein coupled receptor (ADGR) subfamily. {ECO:0000305}.
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DR EMBL; CR855861; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; FQ377894; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR AlphaFoldDB; E7FBY6; -.
DR STRING; 7955.ENSDARP00000103078; -.
DR PaxDb; E7FBY6; -.
DR Ensembl; ENSDART00000112331; ENSDARP00000103078; ENSDARG00000076994.
DR ZFIN; ZDB-GENE-081104-363; adgra2.
DR eggNOG; KOG0619; Eukaryota.
DR GeneTree; ENSGT00940000158941; -.
DR InParanoid; E7FBY6; -.
DR TreeFam; TF331206; -.
DR PRO; PR:E7FBY6; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 8.
DR Bgee; ENSDARG00000076994; Expressed in heart and 14 other tissues.
DR ExpressionAtlas; E7FBY6; baseline.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:1990909; C:Wnt signalosome; IDA:UniProtKB.
DR GO; GO:0004930; F:G protein-coupled receptor activity; IEA:UniProtKB-KW.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0007417; P:central nervous system development; IBA:GO_Central.
DR GO; GO:0022009; P:central nervous system vasculogenesis; IMP:ZFIN.
DR GO; GO:1990791; P:dorsal root ganglion development; IMP:ZFIN.
DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IDA:UniProtKB.
DR GO; GO:0002040; P:sprouting angiogenesis; IMP:ZFIN.
DR GO; GO:0001944; P:vasculature development; IMP:ZFIN.
DR GO; GO:0016055; P:Wnt signaling pathway; IMP:ZFIN.
DR Gene3D; 2.60.220.50; -; 1.
DR Gene3D; 2.60.40.10; -; 1.
DR Gene3D; 3.80.10.10; -; 2.
DR Gene3D; 4.10.1240.10; -; 1.
DR InterPro; IPR000483; Cys-rich_flank_reg_C.
DR InterPro; IPR046338; GAIN_dom_sf.
DR InterPro; IPR017981; GPCR_2-like.
DR InterPro; IPR036445; GPCR_2_extracell_dom_sf.
DR InterPro; IPR001879; GPCR_2_extracellular_dom.
DR InterPro; IPR000832; GPCR_2_secretin-like.
DR InterPro; IPR000203; GPS.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp.
DR InterPro; IPR032675; LRR_dom_sf.
DR Pfam; PF00002; 7tm_2; 1.
DR Pfam; PF13895; Ig_2; 1.
DR Pfam; PF00560; LRR_1; 1.
DR Pfam; PF13855; LRR_8; 1.
DR SMART; SM00409; IG; 1.
DR SMART; SM00369; LRR_TYP; 4.
DR SMART; SM00082; LRRCT; 1.
DR SUPFAM; SSF111418; SSF111418; 1.
DR SUPFAM; SSF48726; SSF48726; 1.
DR PROSITE; PS50227; G_PROTEIN_RECEP_F2_3; 1.
DR PROSITE; PS50261; G_PROTEIN_RECEP_F2_4; 1.
DR PROSITE; PS50221; GPS; 1.
DR PROSITE; PS50835; IG_LIKE; 1.
DR PROSITE; PS51450; LRR; 4.
PE 1: Evidence at protein level;
KW Angiogenesis; Cell membrane; Disulfide bond; G-protein coupled receptor;
KW Glycoprotein; Immunoglobulin domain; Leucine-rich repeat; Membrane;
KW Neurogenesis; Receptor; Reference proteome; Repeat; Signal; Transducer;
KW Transmembrane; Transmembrane helix; Wnt signaling pathway.
FT SIGNAL 1..26
FT /evidence="ECO:0000255"
FT CHAIN 27..1367
FT /note="Adhesion G protein-coupled receptor A2"
FT /evidence="ECO:0000255"
FT /id="PRO_5006465473"
FT TOPO_DOM 27..742
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q91ZV8"
FT TRANSMEM 743..763
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 764..783
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 784..804
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 805..809
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 810..830
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 831..858
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 859..879
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 880..896
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 897..917
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 918..982
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 983..1003
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1004..1011
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1012..1032
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1033..1367
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q91ZV8"
FT REPEAT 70..94
FT /note="LRR 1"
FT /evidence="ECO:0000255"
FT REPEAT 95..118
FT /note="LRR 2"
FT /evidence="ECO:0000255"
FT REPEAT 119..142
FT /note="LRR 3"
FT /evidence="ECO:0000255"
FT REPEAT 144..166
FT /note="LRR 4"
FT /evidence="ECO:0000255"
FT DOMAIN 178..228
FT /note="LRRCT"
FT /evidence="ECO:0000255"
FT DOMAIN 230..332
FT /note="Ig-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DOMAIN 678..729
FT /note="GPS"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00098"
FT REGION 938..958
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1126..1156
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1221..1271
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1339..1367
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 1364..1367
FT /note="PDZ-binding"
FT /evidence="ECO:0000250|UniProtKB:Q96PE1"
FT COMPBIAS 1227..1241
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 356..357
FT /note="Cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q96PE1"
FT CARBOHYD 72
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 78
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 89
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 145
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 150
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 324
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 424
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 582
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 632
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 661
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT DISULFID 256..316
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT MUTAGEN 126..149
FT /note="Missing: In ouchless mutant; cerebrovascular defects
FT characterized by impaired dorsal root ganglia formation in
FT larvae. Defects are caused by accumulation of the protein
FT in the endoplasmic reticulum and inability to reach the
FT plasma membrane."
FT /evidence="ECO:0000269|PubMed:27979830,
FT ECO:0000269|PubMed:27979884"
SQ SEQUENCE 1367 AA; 149498 MW; 6C101E3C57DEF7D8 CRC64;
MSGPCVRIPF WVRVFLLLLL YRIAAGCPEL FSSGCSCTED RSKAHPTPGT RRKVSCGGKE
LTETPEVSLL PNRTVSLNLS NNRIRMLKNG SFAGLSSLEK LDLRNNLIST IMPGAFLGLT
ALRKLDLSSN RIGCLTPEMF QGLTNLTKLN ISGNIFSSLD PNVFMELHSL KLVNFHSEFL
SCDCGLRWVP SFFRSGSARL GDETLCAYPR RLQNKPLRLL RESDLSCEGP LELHTLSLLP
SQRQVVFKGD RLPFHCTASL VDKITALHWR QNGQPVTSDP TKGIHLEESV QHDCTFITSE
LILSNVHVEA SGEWECVVST GRGNTSCSVE IVVLENSASF CPEQKVNNNR GEFRWPRTLA
GITSYQHCLQ LRYPSLTLGG GVEQKKASRN CDRSGRWEEA DYSQCLYTND ITRILHTFIL
MPVNASNAVT LAHQVRSYTL EAAGFTDTVD VLYVAQMMHK FMDYVTELRE LSEVLVEMGS
NLMQVDDQIL ARAQREERAC SSIVYTLETL AWPQLHSHAQ DLSRYSRNIV MEAHLIRPAH
FTGISCTVYQ RREGAAGSQV HDGADLSLEQ QLRFRCTTGT HNTSLNAFHL KNAVALATVS
LPATLFPPNA PPDCKLQFVA FRNGRFFPFT SNFTGHSDLA RRRGISTPVI YAGLDGCSMW
NQSDPIIVSL RHTSPGHDPV AAHWNSQALG HHGSWSLDGC QLIHSDVSIS TLRCSVLSNY
AVLQEIPDFP GSPSIPVEVL HPVIYTCTAV LLLCLFTIII TYILHHSSIR ITRKSWHTLL
NTSFHVAMTS AVFAGGITLT GYPIVCQAVG IVLHYSSLST LLWIGVSARV IYKEALLRTP
QQLEGESAVQ PTQRPMLRFY LIAGGVPLII CGITAAVNIN NYGDNIPYCW LVWQPSFGAF
YIPAGLIILV TWIYFLCTVF CLRQRNFQES KDLQCSASDP SNLPESQPAL SGSTSLLSTD
SGVSPVHAGT TVEDQYSLKV QCLALMATQF VFVGLWCCGA MAVWHVDRER KLFSCLYGGT
ATGLGIFLVL HHCFKRLDVQ AAWLGCCPGY HRSQPMPAYS HPCTVTVGVQ SASERGSQLF
VACHPPTDPN HYSSSARSSS TQSGTASITV VPSKLTNLLQ VSQDNANNAS RAPAGTNTNT
STSTENNKPT NNLLPSLLPV QQPQRRKACS RTKGGNTQYH HRGDARSHYR LKALRAGGGG
SMGALGPSGT EHSNIYHVHK HASSENGSLR NSHSEGQNGL LTNGRHRGEG LATSPSEGSD
GGSSGSRKPF PLLPSVARRA AMQQNAQCRS ASKDNLKLAA AAERESKRSS FPLNMSSNVT
ATASLSTVSA PNGTLKGSVV ELDTSGTDQS QGSVGMKSRV WKSETTV
