ID   GFRA2_HUMAN             Reviewed;         464 AA.
AC   O00451; E9PD47; O15316; O15328; Q58J92; Q6GTR9; Q7Z5C2;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   31-OCT-2006, sequence version 2.
DT   24-JAN-2024, entry version 183.
DE   RecName: Full=GDNF family receptor alpha-2;
DE            Short=GDNF receptor alpha-2;
DE            Short=GDNFR-alpha-2;
DE            Short=GFR-alpha-2;
DE   AltName: Full=GDNF receptor beta;
DE            Short=GDNFR-beta;
DE   AltName: Full=Neurturin receptor alpha;
DE            Short=NRTNR-alpha;
DE            Short=NTNR-alpha;
DE   AltName: Full=RET ligand 2;
DE   AltName: Full=TGF-beta-related neurotrophic factor receptor 2;
DE   Flags: Precursor;
GN   Name=GFRA2; Synonyms=GDNFRB, RETL2, TRNR2;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND VARIANT GLN-462.
RX   PubMed=9182803; DOI=10.1016/s0896-6273(00)80318-9;
RA   Baloh R.H., Tansey M.G., Golden J.P., Creedon D.J., Heuckeroth R.O.,
RA   Keck C.L., Zimonjic D.B., Popescu N.C., Johnson E.M. Jr., Milbrandt J.;
RT   "TrnR2, a novel receptor that mediates neurturin and GDNF signaling through
RT   Ret.";
RL   Neuron 18:793-802(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT GLN-462.
RC   TISSUE=Fetal brain;
RX   PubMed=9259272; DOI=10.1093/hmg/6.8.1267;
RA   Suvanto P., Wartiovaara K., Lindahl M., Arumae U., Moshnyakov M.,
RA   Horelli-Kuitunen N., Airaksinen M.S., Palotie A., Sariola H., Saarma M.;
RT   "Cloning, mRNA distribution and chromosomal localisation of the gene for
RT   glial cell line-derived neurotrophic factor receptor beta, a homologue to
RT   GDNFR-alpha.";
RL   Hum. Mol. Genet. 6:1267-1273(1997).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC   TISSUE=Liver;
RX   PubMed=9177201; DOI=10.1073/pnas.94.12.6238;
RA   Sanicola M., Hession C.A., Worley D.S., Carmillo P., Ehrenfels C.,
RA   Walus L., Robinson S., Jaworski G., Wei H., Tizard R., Whitty A.,
RA   Pepinsky R.B., Cate R.L.;
RT   "Glial cell line-derived neurotrophic factor-dependent RET activation can
RT   be mediated by two different cell-surface accessory proteins.";
RL   Proc. Natl. Acad. Sci. U.S.A. 94:6238-6243(1997).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), AND VARIANT GLN-462.
RA   Yoong L.F., Too H.P.;
RL   Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16421571; DOI=10.1038/nature04406;
RA   Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA   Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA   Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA   Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA   Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA   Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA   Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA   Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA   Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA   O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA   Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA   Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA   Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA   Platzer M., Shimizu N., Lander E.S.;
RT   "DNA sequence and analysis of human chromosome 8.";
RL   Nature 439:331-335(2006).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [7]
RP   INTERACTION WITH SORL1.
RX   PubMed=23333276; DOI=10.1016/j.celrep.2012.12.011;
RA   Glerup S., Lume M., Olsen D., Nyengaard J.R., Vaegter C.B., Gustafsen C.,
RA   Christensen E.I., Kjolby M., Hay-Schmidt A., Bender D., Madsen P.,
RA   Saarma M., Nykjaer A., Petersen C.M.;
RT   "SorLA controls neurotrophic activity by sorting of GDNF and its receptors
RT   GFRalpha1 and RET.";
RL   Cell Rep. 3:186-199(2013).
CC   -!- FUNCTION: Receptor for neurturin. Mediates the NRTN-induced
CC       autophosphorylation and activation of the RET receptor. Also able to
CC       mediate GDNF signaling through the RET tyrosine kinase receptor.
CC   -!- FUNCTION: [Isoform 2]: Participates in NRTN-induced 'Ser-727'
CC       phosphorylation of STAT3. {ECO:0000250|UniProtKB:O08842}.
CC   -!- SUBUNIT: Interacts with SORL1. {ECO:0000269|PubMed:23333276}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Lipid-anchor, GPI-
CC       anchor {ECO:0000250}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1; Synonyms=Long;
CC         IsoId=O00451-1; Sequence=Displayed;
CC       Name=2; Synonyms=Short;
CC         IsoId=O00451-2; Sequence=VSP_001661;
CC       Name=3;
CC         IsoId=O00451-3; Sequence=VSP_046112;
CC   -!- TISSUE SPECIFICITY: Isoform 1 is found in both brain and placenta.
CC   -!- SIMILARITY: Belongs to the GDNFR family. {ECO:0000305}.
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DR   EMBL; AF002700; AAC52036.1; -; mRNA.
DR   EMBL; U93703; AAB61922.1; -; mRNA.
DR   EMBL; U97145; AAC51647.1; -; mRNA.
DR   EMBL; AY326396; AAP88378.1; -; mRNA.
DR   EMBL; AY941828; AAX46325.1; -; mRNA.
DR   EMBL; AC105186; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC129925; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AP008236; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC041688; AAH41688.1; -; mRNA.
DR   CCDS; CCDS47816.1; -. [O00451-1]
DR   CCDS; CCDS55207.1; -. [O00451-2]
DR   CCDS; CCDS55208.1; -. [O00451-3]
DR   RefSeq; NP_001158510.1; NM_001165038.1. [O00451-3]
DR   RefSeq; NP_001158511.1; NM_001165039.1. [O00451-2]
DR   RefSeq; NP_001486.4; NM_001495.4. [O00451-1]
DR   RefSeq; XP_006716390.1; XM_006716327.3. [O00451-1]
DR   RefSeq; XP_011542786.1; XM_011544484.2. [O00451-1]
DR   PDB; 5MR4; X-ray; 2.40 A; C/D=1-458.
DR   PDB; 5MR5; X-ray; 2.00 A; C/D=147-362.
DR   PDB; 6GL7; EM; 6.30 A; C/D=22-441.
DR   PDB; 6Q2O; EM; 3.65 A; C/D=24-362.
DR   PDB; 6Q2R; EM; 4.30 A; C/D/W/X=24-362.
DR   PDBsum; 5MR4; -.
DR   PDBsum; 5MR5; -.
DR   PDBsum; 6GL7; -.
DR   PDBsum; 6Q2O; -.
DR   PDBsum; 6Q2R; -.
DR   AlphaFoldDB; O00451; -.
DR   EMDB; EMD-0026; -.
DR   EMDB; EMD-20576; -.
DR   EMDB; EMD-20578; -.
DR   SMR; O00451; -.
DR   BioGRID; 108943; 4.
DR   STRING; 9606.ENSP00000428518; -.
DR   GlyCosmos; O00451; 5 sites, 3 glycans.
DR   GlyGen; O00451; 6 sites, 4 O-linked glycans (3 sites).
DR   iPTMnet; O00451; -.
DR   PhosphoSitePlus; O00451; -.
DR   BioMuta; GFRA2; -.
DR   MassIVE; O00451; -.
DR   PaxDb; 9606-ENSP00000428518; -.
DR   PeptideAtlas; O00451; -.
DR   ProteomicsDB; 19584; -.
DR   ProteomicsDB; 47897; -. [O00451-1]
DR   ProteomicsDB; 47898; -. [O00451-2]
DR   Antibodypedia; 5212; 443 antibodies from 35 providers.
DR   DNASU; 2675; -.
DR   Ensembl; ENST00000517328.5; ENSP00000429445.1; ENSG00000168546.11. [O00451-1]
DR   Ensembl; ENST00000517892.5; ENSP00000429979.1; ENSG00000168546.11. [O00451-3]
DR   Ensembl; ENST00000518077.5; ENSP00000429206.1; ENSG00000168546.11. [O00451-2]
DR   Ensembl; ENST00000524240.6; ENSP00000428518.1; ENSG00000168546.11. [O00451-1]
DR   GeneID; 2675; -.
DR   KEGG; hsa:2675; -.
DR   MANE-Select; ENST00000524240.6; ENSP00000428518.1; NM_001495.5; NP_001486.4.
DR   UCSC; uc003wzu.2; human. [O00451-1]
DR   AGR; HGNC:4244; -.
DR   CTD; 2675; -.
DR   DisGeNET; 2675; -.
DR   GeneCards; GFRA2; -.
DR   HGNC; HGNC:4244; GFRA2.
DR   HPA; ENSG00000168546; Tissue enhanced (testis, thyroid gland).
DR   MIM; 601956; gene.
DR   neXtProt; NX_O00451; -.
DR   OpenTargets; ENSG00000168546; -.
DR   PharmGKB; PA28654; -.
DR   VEuPathDB; HostDB:ENSG00000168546; -.
DR   eggNOG; ENOG502QS3P; Eukaryota.
DR   GeneTree; ENSGT00940000156168; -.
DR   HOGENOM; CLU_040179_1_1_1; -.
DR   InParanoid; O00451; -.
DR   OMA; DTGKPCN; -.
DR   OrthoDB; 3899332at2759; -.
DR   PhylomeDB; O00451; -.
DR   TreeFam; TF331647; -.
DR   PathwayCommons; O00451; -.
DR   Reactome; R-HSA-419037; NCAM1 interactions.
DR   Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
DR   Reactome; R-HSA-8853659; RET signaling.
DR   SignaLink; O00451; -.
DR   SIGNOR; O00451; -.
DR   BioGRID-ORCS; 2675; 14 hits in 1146 CRISPR screens.
DR   ChiTaRS; GFRA2; human.
DR   GeneWiki; GFRA2_(gene); -.
DR   GenomeRNAi; 2675; -.
DR   Pharos; O00451; Tbio.
DR   PRO; PR:O00451; -.
DR   Proteomes; UP000005640; Chromosome 8.
DR   RNAct; O00451; Protein.
DR   Bgee; ENSG00000168546; Expressed in secondary oocyte and 128 other cell types or tissues.
DR   ExpressionAtlas; O00451; baseline and differential.
DR   GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central.
DR   GO; GO:0019898; C:extrinsic component of membrane; TAS:ProtInc.
DR   GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR   GO; GO:0043235; C:receptor complex; IBA:GO_Central.
DR   GO; GO:0016167; F:glial cell-derived neurotrophic factor receptor activity; IBA:GO_Central.
DR   GO; GO:0007399; P:nervous system development; IBA:GO_Central.
DR   GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; TAS:ProtInc.
DR   Gene3D; 1.10.220.110; GDNF binding domain; 1.
DR   InterPro; IPR016017; GDNF/GAS1.
DR   InterPro; IPR037193; GDNF_alpha.
DR   InterPro; IPR003438; GDNF_rcpt.
DR   InterPro; IPR003504; GDNF_rcpt_a2.
DR   InterPro; IPR017372; Glial_neurotroph_fac_rcpt_a1/2.
DR   PANTHER; PTHR10269:SF4; GDNF FAMILY RECEPTOR ALPHA-2; 1.
DR   PANTHER; PTHR10269; GDNF RECEPTOR ALPHA; 1.
DR   Pfam; PF02351; GDNF; 3.
DR   PIRSF; PIRSF038071; GDNF_family_receptor_alpha; 1.
DR   PRINTS; PR01318; GDNFRALPHA2.
DR   PRINTS; PR01316; GDNFRECEPTOR.
DR   SMART; SM00907; GDNF; 3.
DR   SUPFAM; SSF110035; GDNF receptor-like; 1.
DR   Genevisible; O00451; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Cell membrane; Glycoprotein;
KW   GPI-anchor; Lipoprotein; Membrane; Receptor; Reference proteome; Signal.
FT   SIGNAL          1..21
FT                   /evidence="ECO:0000255"
FT   CHAIN           22..444
FT                   /note="GDNF family receptor alpha-2"
FT                   /id="PRO_0000010785"
FT   PROPEP          445..464
FT                   /note="Removed in mature form"
FT                   /evidence="ECO:0000255"
FT                   /id="PRO_0000010786"
FT   REGION          363..392
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        363..378
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   LIPID           444
FT                   /note="GPI-anchor amidated serine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        52
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        357
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        413
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   VAR_SEQ         14..146
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:9182803, ECO:0000303|Ref.4"
FT                   /id="VSP_001661"
FT   VAR_SEQ         14..118
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|Ref.4"
FT                   /id="VSP_046112"
FT   VARIANT         462
FT                   /note="L -> Q (in dbSNP:rs1128397)"
FT                   /evidence="ECO:0000269|PubMed:9182803,
FT                   ECO:0000269|PubMed:9259272, ECO:0000269|Ref.4"
FT                   /id="VAR_059976"
FT   CONFLICT        6
FT                   /note="V -> A (in Ref. 2; AAB61922)"
FT                   /evidence="ECO:0000305"
FT   HELIX           40..48
FT                   /evidence="ECO:0007829|PDB:5MR4"
FT   HELIX           51..64
FT                   /evidence="ECO:0007829|PDB:5MR4"
FT   HELIX           76..86
FT                   /evidence="ECO:0007829|PDB:5MR4"
FT   TURN            89..92
FT                   /evidence="ECO:0007829|PDB:5MR4"
FT   HELIX           102..111
FT                   /evidence="ECO:0007829|PDB:5MR4"
FT   HELIX           160..169
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   HELIX           172..186
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   STRAND          193..195
FT                   /evidence="ECO:0007829|PDB:5MR4"
FT   HELIX           197..210
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   HELIX           213..220
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   HELIX           227..235
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   HELIX           239..242
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   HELIX           251..260
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   HELIX           262..275
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   STRAND          279..281
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   HELIX           286..288
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   HELIX           290..298
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   TURN            299..302
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   STRAND          307..309
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   STRAND          314..316
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   STRAND          319..322
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   HELIX           329..331
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   HELIX           332..343
FT                   /evidence="ECO:0007829|PDB:5MR5"
FT   HELIX           346..355
FT                   /evidence="ECO:0007829|PDB:5MR5"
SQ   SEQUENCE   464 AA;  51544 MW;  8BC61529530FF21F CRC64;
     MILANVFCLF FFLDETLRSL ASPSSLQGPE LHGWRPPVDC VRANELCAAE SNCSSRYRTL
     RQCLAGRDRN TMLANKECQA ALEVLQESPL YDCRCKRGMK KELQCLQIYW SIHLGLTEGE
     EFYEASPYEP VTSRLSDIFR LASIFSGTGA DPVVSAKSNH CLDAAKACNL NDNCKKLRSS
     YISICNREIS PTERCNRRKC HKALRQFFDR VPSEYTYRML FCSCQDQACA ERRRQTILPS
     CSYEDKEKPN CLDLRGVCRT DHLCRSRLAD FHANCRASYQ TVTSCPADNY QACLGSYAGM
     IGFDMTPNYV DSSPTGIVVS PWCSCRGSGN MEEECEKFLR DFTENPCLRN AIQAFGNGTD
     VNVSPKGPSF QATQAPRVEK TPSLPDDLSD STSLGTSVIT TCTSVQEQGL KANNSKELSM
     CFTELTTNII PGSNKVIKPN SGPSRARPSA ALTVLSVLML KLAL
//