ID GDNF_HUMAN Reviewed; 211 AA. AC P39905; B7WPK7; O95448; O95449; O95986; Q6FH33; Q96L44; Q9UD32; Q9UD33; AC Q9UMV2; Q9UP67; Q9UP97; DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1995, sequence version 1. DT 27-MAR-2024, entry version 221. DE RecName: Full=Glial cell line-derived neurotrophic factor; DE Short=hGDNF; DE AltName: Full=Astrocyte-derived trophic factor; DE Short=ATF; DE Flags: Precursor; GN Name=GDNF; 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 [GENOMIC DNA], FUNCTION, HOMODIMERIZATION, AND RP DISULFIDE BONDS. RX PubMed=8493557; DOI=10.1126/science.8493557; RA Lin L.-F.H., Doherty D.H., Lile J.D., Bektesh S., Collins F.; RT "GDNF: a glial cell line-derived neurotrophic factor for midbrain RT dopaminergic neurons."; RL Science 260:1130-1132(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND TISSUE SPECIFICITY. RX PubMed=7867768; DOI=10.1006/exnr.1994.1218; RA Schaar D.G., Sieber B.-A., Sherwood A.C., Dean D., Mendoza G., RA Ramakrishnan L., Dreyfus C.F., Black I.B.; RT "Multiple astrocyte transcripts encode nigral trophic factors in rat and RT human."; RL Exp. Neurol. 130:387-393(1994). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RA Zhang B., Feng Z., Zhou Y., Peng X., Yuan J., Qiang B.; RL Submitted (AUG-2001) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). 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 [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-187 (ISOFORM 1). RC TISSUE=Fetal kidney; RX PubMed=10366742; DOI=10.1016/s0169-328x(99)00106-0; RA Baecker P.A., Lee W.H., Verity A.N., Eglen R.M., Johnson R.M.; RT "Characterization of a promoter for the human glial cell line-derived RT neurotrophic factor gene."; RL Brain Res. Mol. Brain Res. 69:209-222(1999). RN [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-88 (ISOFORM 2), NUCLEOTIDE SEQUENCE RP [GENOMIC DNA] OF 1-77, AND NUCLEOTIDE SEQUENCE [MRNA] OF 1-59 (ISOFORMS 3 RP AND 4). RC TISSUE=Brain, and Kidney; RA Suter-Crazzolara C., Baecker P.A., Lee W.H., Johnson R.M., Unsicker K.; RT "The human GDNF gene promoter."; RL Submitted (OCT-1997) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-50, SUBCELLULAR LOCATION, AND RP INDUCTION. RX PubMed=9811930; DOI=10.1093/hmg/7.12.1873; RA Grimm L., Holinski-Feder E., Teodoridis J., Scheffer B., Schindelhauer D., RA Meitinger T., Ueffing M.; RT "Analysis of the human GDNF gene reveals an inducible promoter, three RT exons, a triplet repeat within the 3'-UTR and alternative splice RT products."; RL Hum. Mol. Genet. 7:1873-1886(1998). RN [11] RP PROTEIN SEQUENCE OF 87-122; 141-153; 173-184 AND 196-211, HOMODIMERIZATION, RP AND DISULFIDE BONDS. RX PubMed=8988018; DOI=10.1021/bi9605550; RA Haniu M., Hui J., Young Y., Le J., Katta V., Lee R., Shimamoto G., RA Rohde M.F.; RT "Glial cell line-derived neurotrophic factor: selective reduction of the RT intermolecular disulfide linkage and characterization of its disulfide RT structure."; RL Biochemistry 35:16799-16805(1996). RN [12] RP POSSIBLE INVOLVEMENT IN PCC, AND VARIANT TRP-93. RX PubMed=9215674; DOI=10.1093/hmg/6.7.1051; RA Woodward E.R., Eng C., McMahon R., Voutilainen R., Affara N.A., RA Ponder B.A., Maher E.R.; RT "Genetic predisposition to phaeochromocytoma: analysis of candidate genes RT GDNF, RET and VHL."; RL Hum. Mol. Genet. 6:1051-1056(1997). RN [13] RP INTERACTION WITH SORL1. RX PubMed=15364913; DOI=10.1074/jbc.m408873200; RA Westergaard U.B., Soerensen E.S., Hermey G., Nielsen M.S., Nykjaer A., RA Kirkegaard K., Jacobsen C., Gliemann J., Madsen P., Petersen C.M.; RT "Functional organization of the sortilin Vps10p domain."; RL J. Biol. Chem. 279:50221-50229(2004). RN [14] RP INTERACTION WITH SORL1 AND RET, AND SUBCELLULAR LOCATION. RX PubMed=21994944; DOI=10.1074/jbc.m111.246413; RA Geng Z., Xu F.Y., Huang S.H., Chen Z.Y.; RT "Sorting protein-related receptor SorLA controls regulated secretion of RT glial cell line-derived neurotrophic factor."; RL J. Biol. Chem. 286:41871-41882(2011). RN [15] RP ALTERNATIVE SPLICING (ISOFORMS 1; 2; 3 AND 5), AND TISSUE SPECIFICITY. RX PubMed=22081608; DOI=10.1074/jbc.m111.310250; RA Airavaara M., Pletnikova O., Doyle M.E., Zhang Y.E., Troncoso J.C., RA Liu Q.R.; RT "Identification of novel GDNF isoforms and cis-antisense GDNFOS gene and RT their regulation in human middle temporal gyrus of Alzheimer disease."; RL J. Biol. Chem. 286:45093-45102(2011). RN [16] RP REVIEW ON VARIANTS. RX PubMed=9359036; RA Hofstra R.M.W., Osinga J., Buys C.H.C.M.; RT "Mutations in Hirschsprung disease: when does a mutation contribute to the RT phenotype."; RL Eur. J. Hum. Genet. 5:180-185(1997). RN [17] 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). RN [18] RP X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 78-211, GLYCOSYLATION AT ASN-126, RP AND DISULFIDE BONDS. RX PubMed=19478429; DOI=10.1107/s1744309109017722; RA Parkash V., Goldman A.; RT "Comparison of GFL-GFRalpha complexes: further evidence relating GFL bend RT angle to RET signalling."; RL Acta Crystallogr. F 65:551-558(2009). RN [19] RP VARIANT HSCR3 SER-154. RX PubMed=8968758; DOI=10.1093/hmg/5.12.2023; RA Ivanchuk S.M., Myers S.M., Eng C., Mulligan L.M.; RT "De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, RT in Hirschsprung disease."; RL Hum. Mol. Genet. 5:2023-2026(1996). RN [20] RP VARIANT TRP-93. RX PubMed=8896568; DOI=10.1038/ng1196-341; RA Angrist M., Bolk S., Halushka M., Lapchak P.A., Chakravarti A.; RT "Germline mutations in glial cell line-derived neurotrophic factor (GDNF) RT and RET in a Hirschsprung disease patient."; RL Nat. Genet. 14:341-344(1996). RN [21] RP VARIANT HSCR3 SER-21, AND VARIANT ASN-150. RX PubMed=8896569; DOI=10.1038/ng1196-345; RA Salomon R., Attie T., Pelet A., Bidaud C., Eng C., Amiel J., Sarnacki S., RA Goulet O., Ricour C., Nihoul-Fekete C., Munnich A., Lyonnet S.; RT "Germline mutations of the RET ligand GDNF are not sufficient to cause RT Hirschsprung disease."; RL Nat. Genet. 14:345-347(1996). RN [22] RP VARIANT TRP-93. RX PubMed=9497256; DOI=10.1086/301759; RA Amiel J., Salomon R., Attie T., Pelet A., Trang H., Mokhtari M., RA Gaultier C., Munnich A., Lyonnet S.; RT "Mutations of the RET-GDNF signaling pathway in Ondine's curse."; RL Am. J. Hum. Genet. 62:715-717(1998). RN [23] RP VARIANT HSCR3 MET-211. RX PubMed=10917288; DOI=10.1053/jpsu.2000.7763; RA Martucciello G., Ceccherini I., Lerone M., Jasonni V.; RT "Pathogenesis of Hirschsprung's disease."; RL J. Pediatr. Surg. 35:1017-1025(2000). CC -!- FUNCTION: Neurotrophic factor that enhances survival and morphological CC differentiation of dopaminergic neurons and increases their high- CC affinity dopamine uptake. {ECO:0000269|PubMed:8493557}. CC -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:8493557, PubMed:8988018, CC PubMed:19478429). Interacts with RET (PubMed:21994944). Interacts (via CC propeptide) with SORL1 (via N-terminal ectodomain); this interaction CC affects GDNF-regulated, but not constitutive secretion CC (PubMed:15364913, PubMed:21994944, PubMed:23333276). Also interacts CC with SORL1 in complex with GFRA1; this interaction leads to GDNF CC endocytosis and lysosomal degradation (PubMed:23333276). CC {ECO:0000269|PubMed:15364913, ECO:0000269|PubMed:19478429, CC ECO:0000269|PubMed:21994944, ECO:0000269|PubMed:23333276, CC ECO:0000269|PubMed:8493557, ECO:0000269|PubMed:8988018}. CC -!- INTERACTION: CC P39905; Q6RW13: AGTRAP; NbExp=3; IntAct=EBI-10207709, EBI-741181; CC P39905-3; P15941-11: MUC1; NbExp=3; IntAct=EBI-12702062, EBI-17263240; CC P39905-3; Q8TAC9: SCAMP5; NbExp=3; IntAct=EBI-12702062, EBI-2695784; CC P39905-3; P08247: SYP; NbExp=3; IntAct=EBI-12702062, EBI-9071725; CC PRO_0000034005; Q92673: SORL1; NbExp=6; IntAct=EBI-25397146, EBI-1171329; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:21994944, CC ECO:0000269|PubMed:9811930}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=5; CC Name=1; Synonyms=Ex1_4L; CC IsoId=P39905-1; Sequence=Displayed; CC Name=2; Synonyms=ATF-1, Ex1_4S, Ex3_4S, GDNF delta 78 CC {ECO:0000303|PubMed:21994944}, HFK2-GDNF; CC IsoId=P39905-2; Sequence=VSP_006420; CC Name=3; Synonyms=Ex2_4L, HFK3-GDNF; CC IsoId=P39905-3; Sequence=VSP_026368; CC Name=4; Synonyms=HFK4-GDNF; CC IsoId=P39905-4; Sequence=VSP_026368, VSP_006420; CC Name=5; Synonyms=Ex4S_5; CC IsoId=P39905-5; Sequence=VSP_042298; CC -!- TISSUE SPECIFICITY: In the brain, predominantly expressed in the CC striatum with highest levels in the caudate and lowest in the putamen. CC Isoform 2 is absent from most tissues except for low levels in CC intestine and kidney. Highest expression of isoform 3 is found in CC pancreatic islets. Isoform 5 is expressed at very low levels in CC putamen, nucleus accumbens, prefrontal cortex, amygdala, hypothalamus CC and intestine. Isoform 3 is up-regulated in the middle temporal gyrus CC of Alzheimer disease patients while isoform 2 shows no change. CC {ECO:0000269|PubMed:22081608, ECO:0000269|PubMed:7867768}. CC -!- INDUCTION: By cAMP, 12-O-tetradecanoylphorbol-13-acetate (TPA) and CC FGF2. {ECO:0000269|PubMed:9811930}. CC -!- DISEASE: Hirschsprung disease 3 (HSCR3) [MIM:613711]: A disorder of CC neural crest development characterized by absence of enteric ganglia CC along a variable length of the intestine. It is the most common cause CC of congenital intestinal obstruction. Early symptoms range from CC complete acute neonatal obstruction, characterized by vomiting, CC abdominal distention and failure to pass stool, to chronic constipation CC in the older child. {ECO:0000269|PubMed:10917288, CC ECO:0000269|PubMed:8896568, ECO:0000269|PubMed:8896569, CC ECO:0000269|PubMed:8968758}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Pheochromocytoma (PCC) [MIM:171300]: A catecholamine-producing CC tumor of chromaffin tissue of the adrenal medulla or sympathetic CC paraganglia. The cardinal symptom, reflecting the increased secretion CC of epinephrine and norepinephrine, is hypertension, which may be CC persistent or intermittent. {ECO:0000269|PubMed:9215674}. Note=The gene CC represented in this entry may act as a disease modifier. CC -!- SIMILARITY: Belongs to the TGF-beta family. GDNF subfamily. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L19063; AAA67910.1; -; Genomic_DNA. DR EMBL; L19062; AAA67910.1; JOINED; Genomic_DNA. DR EMBL; AY052832; AAL11017.1; -; mRNA. DR EMBL; CR541923; CAG46721.1; -; mRNA. DR EMBL; AC008869; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471119; EAW55963.1; -; Genomic_DNA. DR EMBL; BC069119; AAH69119.1; -; mRNA. DR EMBL; BC069369; AAH69369.1; -; mRNA. DR EMBL; BC128108; AAI28109.1; -; mRNA. DR EMBL; BC128109; AAI28110.1; -; mRNA. DR EMBL; AF053748; AAD43139.1; -; mRNA. DR EMBL; AJ001896; CAA05074.1; -; Genomic_DNA. DR EMBL; AJ001897; CAA05075.1; -; mRNA. DR EMBL; AJ001898; CAA05076.1; -; mRNA. DR EMBL; AJ001899; CAA05077.1; -; mRNA. DR EMBL; AJ001900; CAA05078.1; -; mRNA. DR EMBL; AF063586; AAC98782.1; -; Genomic_DNA. DR CCDS; CCDS3922.1; -. [P39905-1] DR CCDS; CCDS3923.1; -. [P39905-2] DR CCDS; CCDS54845.1; -. [P39905-3] DR CCDS; CCDS54846.1; -. [P39905-4] DR CCDS; CCDS75237.1; -. [P39905-5] DR PIR; B37499; B37499. DR RefSeq; NP_000505.1; NM_000514.3. [P39905-1] DR RefSeq; NP_001177397.1; NM_001190468.1. [P39905-3] DR RefSeq; NP_001177398.1; NM_001190469.1. [P39905-4] DR RefSeq; NP_001265027.1; NM_001278098.1. [P39905-5] DR RefSeq; NP_954701.1; NM_199231.2. [P39905-2] DR RefSeq; XP_011512332.1; XM_011514030.2. DR RefSeq; XP_016864826.1; XM_017009337.1. [P39905-2] DR PDB; 2V5E; X-ray; 2.35 A; B=111-211. DR PDB; 3FUB; X-ray; 2.35 A; B/D=78-211. DR PDB; 4UX8; EM; 24.00 A; D/F=78-211. DR PDB; 6Q2N; EM; 4.40 A; A/B=78-211. DR PDBsum; 2V5E; -. DR PDBsum; 3FUB; -. DR PDBsum; 4UX8; -. DR PDBsum; 6Q2N; -. DR AlphaFoldDB; P39905; -. DR EMDB; EMD-20575; -. DR EMDB; EMD-2712; -. DR SMR; P39905; -. DR BioGRID; 108936; 35. DR DIP; DIP-59051N; -. DR IntAct; P39905; 12. DR STRING; 9606.ENSP00000409007; -. DR DrugBank; DB09301; Chondroitin sulfate. DR GlyCosmos; P39905; 2 sites, No reported glycans. DR GlyGen; P39905; 2 sites. DR iPTMnet; P39905; -. DR PhosphoSitePlus; P39905; -. DR BioMuta; GDNF; -. DR DMDM; 729567; -. DR jPOST; P39905; -. DR MassIVE; P39905; -. DR PaxDb; 9606-ENSP00000409007; -. DR ProteomicsDB; 55328; -. [P39905-1] DR ProteomicsDB; 55329; -. [P39905-2] DR ProteomicsDB; 55330; -. [P39905-3] DR ProteomicsDB; 55331; -. [P39905-4] DR ProteomicsDB; 55332; -. [P39905-5] DR TopDownProteomics; P39905-3; -. [P39905-3] DR Antibodypedia; 3924; 635 antibodies from 42 providers. DR DNASU; 2668; -. DR Ensembl; ENST00000326524.7; ENSP00000317145.2; ENSG00000168621.15. [P39905-1] DR Ensembl; ENST00000344622.8; ENSP00000339703.4; ENSG00000168621.15. [P39905-2] DR Ensembl; ENST00000381826.8; ENSP00000371248.4; ENSG00000168621.15. [P39905-4] DR Ensembl; ENST00000427982.5; ENSP00000409007.1; ENSG00000168621.15. [P39905-3] DR Ensembl; ENST00000515058.5; ENSP00000425928.1; ENSG00000168621.15. [P39905-2] DR Ensembl; ENST00000620847.1; ENSP00000478722.1; ENSG00000168621.15. [P39905-5] DR GeneID; 2668; -. DR KEGG; hsa:2668; -. DR MANE-Select; ENST00000326524.7; ENSP00000317145.2; NM_000514.4; NP_000505.1. DR UCSC; uc011cpd.2; human. [P39905-1] DR AGR; HGNC:4232; -. DR CTD; 2668; -. DR DisGeNET; 2668; -. DR GeneCards; GDNF; -. DR HGNC; HGNC:4232; GDNF. DR HPA; ENSG00000168621; Tissue enhanced (intestine, skeletal muscle). DR MalaCards; GDNF; -. DR MIM; 171300; phenotype. DR MIM; 600837; gene. DR MIM; 613711; phenotype. DR neXtProt; NX_P39905; -. DR OpenTargets; ENSG00000168621; -. DR Orphanet; 661; Congenital central hypoventilation syndrome. DR Orphanet; 388; Hirschsprung disease. DR PharmGKB; PA28644; -. DR VEuPathDB; HostDB:ENSG00000168621; -. DR eggNOG; ENOG502QWCH; Eukaryota. DR GeneTree; ENSGT00950000182993; -. DR HOGENOM; CLU_102221_1_0_1; -. DR InParanoid; P39905; -. DR OrthoDB; 5362928at2759; -. DR PhylomeDB; P39905; -. DR TreeFam; TF332366; -. DR PathwayCommons; P39905; -. 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; P39905; -. DR SIGNOR; P39905; -. DR BioGRID-ORCS; 2668; 15 hits in 1146 CRISPR screens. DR ChiTaRS; GDNF; human. DR EvolutionaryTrace; P39905; -. DR GeneWiki; Glial_cell_line-derived_neurotrophic_factor; -. DR GenomeRNAi; 2668; -. DR Pharos; P39905; Tbio. DR PRO; PR:P39905; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; P39905; Protein. DR Bgee; ENSG00000168621; Expressed in hindlimb stylopod muscle and 112 other cell types or tissues. DR ExpressionAtlas; P39905; baseline and differential. DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:1902379; F:chemoattractant activity involved in axon guidance; TAS:ARUK-UCL. DR GO; GO:0030116; F:glial cell-derived neurotrophic factor receptor binding; IEA:InterPro. DR GO; GO:0008083; F:growth factor activity; IBA:GO_Central. DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB. DR GO; GO:0030971; F:receptor tyrosine kinase binding; IEA:InterPro. DR GO; GO:0005102; F:signaling receptor binding; TAS:ProtInc. DR GO; GO:0008344; P:adult locomotory behavior; TAS:BHF-UCL. DR GO; GO:0001658; P:branching involved in ureteric bud morphogenesis; ISS:UniProtKB. DR GO; GO:0071679; P:commissural neuron axon guidance; ISS:ARUK-UCL. DR GO; GO:0021516; P:dorsal spinal cord development; ISS:ARUK-UCL. DR GO; GO:0048568; P:embryonic organ development; ISS:ARUK-UCL. DR GO; GO:0048484; P:enteric nervous system development; ISS:UniProtKB. DR GO; GO:0003337; P:mesenchymal to epithelial transition involved in metanephros morphogenesis; IEA:Ensembl. DR GO; GO:0001656; P:metanephros development; ISS:UniProtKB. DR GO; GO:0048255; P:mRNA stabilization; IDA:BHF-UCL. DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:ProtInc. DR GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IDA:UniProtKB. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:UniProtKB. DR GO; GO:0007399; P:nervous system development; TAS:ARUK-UCL. DR GO; GO:0001755; P:neural crest cell migration; IDA:MGI. DR GO; GO:0031175; P:neuron projection development; IDA:MGI. DR GO; GO:0001759; P:organ induction; IEA:Ensembl. DR GO; GO:0007422; P:peripheral nervous system development; IBA:GO_Central. DR GO; GO:0030432; P:peristalsis; ISS:UniProtKB. DR GO; GO:0090190; P:positive regulation of branching involved in ureteric bud morphogenesis; IDA:UniProtKB. DR GO; GO:0045597; P:positive regulation of cell differentiation; IGI:MGI. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:MGI. DR GO; GO:0033603; P:positive regulation of dopamine secretion; TAS:BHF-UCL. DR GO; GO:0072108; P:positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis; IEA:Ensembl. DR GO; GO:0032770; P:positive regulation of monooxygenase activity; IDA:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL. DR GO; GO:0072107; P:positive regulation of ureteric bud formation; IDA:UniProtKB. DR GO; GO:0021784; P:postganglionic parasympathetic fiber development; ISS:UniProtKB. DR GO; GO:0001941; P:postsynaptic membrane organization; IEA:Ensembl. DR GO; GO:0051584; P:regulation of dopamine uptake involved in synaptic transmission; IDA:UniProtKB. DR GO; GO:0010468; P:regulation of gene expression; IGI:MGI. DR GO; GO:0060688; P:regulation of morphogenesis of a branching structure; ISS:UniProtKB. DR GO; GO:2001260; P:regulation of semaphorin-plexin signaling pathway; ISS:ARUK-UCL. DR GO; GO:2000736; P:regulation of stem cell differentiation; TAS:ParkinsonsUK-UCL. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0048485; P:sympathetic nervous system development; ISS:UniProtKB. DR GO; GO:0060676; P:ureteric bud formation; IEA:Ensembl. DR CDD; cd19380; TGF_beta_GDNF; 1. DR DisProt; DP02574; -. DR Gene3D; 2.10.90.10; Cystine-knot cytokines; 1. DR InterPro; IPR029034; Cystine-knot_cytokine. DR InterPro; IPR016649; GDNF. DR InterPro; IPR043401; GDNF_fam. DR InterPro; IPR047020; GDNF_TGF-b-like. DR InterPro; IPR001839; TGF-b_C. DR PANTHER; PTHR12173; GDNF SUBFAMILY OF TGF-BETA FAMILY; 1. DR PANTHER; PTHR12173:SF1; GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR; 1. DR Pfam; PF00019; TGF_beta; 1. DR PIRSF; PIRSF016238; GDNF; 1. DR SMART; SM00204; TGFB; 1. DR SUPFAM; SSF57501; Cystine-knot cytokines; 1. DR PROSITE; PS51362; TGF_BETA_2; 1. DR Genevisible; P39905; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cleavage on pair of basic residues; KW Direct protein sequencing; Disease variant; Disulfide bond; Glycoprotein; KW Growth factor; Hirschsprung disease; Reference proteome; Secreted; Signal. FT SIGNAL 1..19 FT /evidence="ECO:0000255" FT PROPEP 20..75 FT /evidence="ECO:0000250" FT /id="PRO_0000034004" FT CHAIN 78..211 FT /note="Glial cell line-derived neurotrophic factor" FT /id="PRO_0000034005" FT REGION 21..56 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 78..113 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 126 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19478429" FT CARBOHYD 162 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 118..179 FT /evidence="ECO:0000269|PubMed:8988018" FT DISULFID 145..208 FT /evidence="ECO:0000269|PubMed:8988018" FT DISULFID 149..210 FT /evidence="ECO:0000269|PubMed:8988018" FT DISULFID 178 FT /note="Interchain" FT VAR_SEQ 1..52 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000305" FT /id="VSP_042298" FT VAR_SEQ 1 FT /note="M -> MQSLPNSNGAAAGRDFKM (in isoform 3 and isoform FT 4)" FT /evidence="ECO:0000303|Ref.9" FT /id="VSP_026368" FT VAR_SEQ 25..51 FT /note="GKRPPEAPAEDRSLGRRRAPFALSSDS -> A (in isoform 2 and FT isoform 4)" FT /evidence="ECO:0000303|PubMed:7867768, ECO:0000303|Ref.3, FT ECO:0000303|Ref.9" FT /id="VSP_006420" FT VARIANT 21 FT /note="P -> S (in HSCR3; uncertain significance; FT dbSNP:rs777451569)" FT /evidence="ECO:0000269|PubMed:8896569" FT /id="VAR_009494" FT VARIANT 93 FT /note="R -> W (may be a risk factor for Hirschsprung FT disease; dbSNP:rs36119840)" FT /evidence="ECO:0000269|PubMed:8896568, FT ECO:0000269|PubMed:9215674, ECO:0000269|PubMed:9497256" FT /id="VAR_009495" FT VARIANT 150 FT /note="D -> N (risk factor for Hirschsprung disease; FT dbSNP:rs76466003)" FT /evidence="ECO:0000269|PubMed:8896569" FT /id="VAR_009496" FT VARIANT 154 FT /note="T -> S (in HSCR3; sporadic form; dbSNP:rs104893891)" FT /evidence="ECO:0000269|PubMed:8968758" FT /id="VAR_009497" FT VARIANT 211 FT /note="I -> M (in HSCR3; dbSNP:rs121918536)" FT /evidence="ECO:0000269|PubMed:10917288" FT /id="VAR_018152" FT TURN 114..117 FT /evidence="ECO:0007829|PDB:2V5E" FT STRAND 119..126 FT /evidence="ECO:0007829|PDB:2V5E" FT HELIX 127..130 FT /evidence="ECO:0007829|PDB:2V5E" FT STRAND 139..147 FT /evidence="ECO:0007829|PDB:2V5E" FT HELIX 155..165 FT /evidence="ECO:0007829|PDB:2V5E" FT STRAND 168..173 FT /evidence="ECO:0007829|PDB:2V5E" FT STRAND 178..184 FT /evidence="ECO:0007829|PDB:2V5E" FT STRAND 188..191 FT /evidence="ECO:0007829|PDB:2V5E" FT STRAND 197..200 FT /evidence="ECO:0007829|PDB:2V5E" FT STRAND 204..211 FT /evidence="ECO:0007829|PDB:2V5E" SQ SEQUENCE 211 AA; 23720 MW; A0D1EBF77FC82691 CRC64; MKLWDVVAVC LVLLHTASAF PLPAGKRPPE APAEDRSLGR RRAPFALSSD SNMPEDYPDQ FDDVMDFIQA TIKRLKRSPD KQMAVLPRRE RNRQAAAANP ENSRGKGRRG QRGKNRGCVL TAIHLNVTDL GLGYETKEEL IFRYCSGSCD AAETTYDKIL KNLSRNRRLV SDKVGQACCR PIAFDDDLSF LDDNLVYHIL RKHSAKRCGC I //