ID NRTN_HUMAN Reviewed; 197 AA. AC Q99748; B2RPE8; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1997, sequence version 1. DT 24-JUL-2024, entry version 193. DE RecName: Full=Neurturin {ECO:0000303|PubMed:8945474}; DE Flags: Precursor; GN Name=NRTN {ECO:0000303|PubMed:31535977, ECO:0000312|HGNC:HGNC:8007}; 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], AND FUNCTION. RX PubMed=8945474; DOI=10.1038/384467a0; RA Kotzbauer P.T., Lampe P.A., Heuckeroth R.O., Golden J.P., Creedon D.J., RA Johnson E.M. Jr., Milbrandt J.; RT "Neurturin, a relative of glial-cell-line-derived neurotrophic factor."; RL Nature 384:467-470(1996). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Melanoma; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [3] 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 (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [5] RP FUNCTION. RX PubMed=10829012; DOI=10.1074/jbc.m000306200; RA Cik M., Masure S., Lesage A.S., Van Der Linden I., Van Gompel P., RA Pangalos M.N., Gordon R.D., Leysen J.E.; RT "Binding of GDNF and neurturin to human GDNF family receptor alpha 1 and 2. RT Influence of cRET and cooperative interactions."; RL J. Biol. Chem. 275:27505-27512(2000). RN [6] RP FUNCTION. RX PubMed=15242795; DOI=10.1016/j.ydbio.2004.04.025; RA Yan H., Bergner A.J., Enomoto H., Milbrandt J., Newgreen D.F., Young H.M.; RT "Neural cells in the esophagus respond to glial cell line-derived RT neurotrophic factor and neurturin, and are RET-dependent."; RL Dev. Biol. 272:118-133(2004). RN [7] {ECO:0007744|PDB:5MR4, ECO:0007744|PDB:5MR5, ECO:0007744|PDB:5NMZ} RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 97-197 IN COMPLEX WITH GFRA2, RP FUNCTION, SUBUNIT, DISULFIDE BONDS, AND MUTAGENESIS OF 158-ARG--GLN-162. RX PubMed=29414779; DOI=10.1074/jbc.ra117.000820; RA Sandmark J., Dahl G., Oester L., Xu B., Johansson P., Akerud T., RA Aagaard A., Davidsson P., Bigalke J.M., Winzell M.S., Rainey G.J., RA Roth R.G.; RT "Structure and biophysical characterization of the human full-length RT neurturin-GFRa2 complex: A role for heparan sulfate in signaling."; RL J. Biol. Chem. 293:5492-5508(2018). RN [8] {ECO:0007744|PDB:6Q2O, ECO:0007744|PDB:6Q2R} RP STRUCTURE BY ELECTRON MICROSCOPY (3.65 ANGSTROMS) OF 96-197 IN COMPLEX WITH RP RET AND GFRA2, FUNCTION, SUBUNIT, AND DISULFIDE BONDS. RX PubMed=31535977; DOI=10.7554/elife.47650; RA Li J., Shang G., Chen Y.J., Brautigam C.A., Liou J., Zhang X., Bai X.C.; RT "Cryo-EM analyses reveal the common mechanism and diversification in the RT activation of RET by different ligands."; RL Elife 8:0-0(2019). RN [9] RP VARIANT SER-96, AND POSSIBLE INVOLVEMENT IN HIRSCHSPRUNG DISEASE. RC TISSUE=Peripheral blood lymphocyte; RX PubMed=9700200; DOI=10.1093/hmg/7.9.1449; RA Doray B., Salomon R., Amiel J., Pelet A., Touraine R., Billaud M., RA Attie T., Bachy B., Munnich A., Lyonnet S.; RT "Mutation of the RET ligand, neurturin, supports multigenic inheritance in RT Hirschsprung disease."; RL Hum. Mol. Genet. 7:1449-1452(1998). CC -!- FUNCTION: Growth factor that supports the survival of sympathetic CC neurons in culture (PubMed:8945474). May regulate the development and CC maintenance of the CNS (PubMed:8945474). Involved in the development of CC the neural crest (PubMed:15242795). Might control the size of non- CC neuronal cell population such as haemopoietic cells (PubMed:8945474). CC Acts by binding to its coreceptor, GFRA2, leading to CC autophosphorylation and activation of the RET receptor CC (PubMed:10829012, PubMed:29414779, PubMed:31535977). Heparan sulfate- CC binding is required for signaling (PubMed:29414779). CC {ECO:0000269|PubMed:10829012, ECO:0000269|PubMed:15242795, CC ECO:0000269|PubMed:29414779, ECO:0000269|PubMed:31535977, CC ECO:0000269|PubMed:8945474}. CC -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:29414779, CC PubMed:31535977). Interacts with GFRA2 coreceptor and RET: forms a CC 2:2:2 ternary complex composed of NRTN ligand, GFRA2 and RET receptor CC (PubMed:31535977). Also forms a 4:4:4 tetrameric complex composed of 4 CC copies of NRTN ligand, GFRA2 and RET receptor, which prevents CC endocytosis of RET (PubMed:31535977). {ECO:0000269|PubMed:29414779, CC ECO:0000269|PubMed:31535977}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P97463}. CC -!- DISEASE: Note=Genetic variations in NRTN may contribute to Hirschsprung CC disease, in association with mutations of RET gene, and possibly CC mutations in other loci. Hirschsprung disease is a disorder of neural CC crest development is characterized by the absence of intramural CC ganglion cells in the hindgut, often resulting in intestinal CC obstruction. {ECO:0000269|PubMed:9700200}. 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; U78110; AAC50898.1; -; mRNA. DR EMBL; AL161995; CAB82327.1; -; mRNA. DR EMBL; CH471139; EAW69140.1; -; Genomic_DNA. DR EMBL; BC137399; AAI37400.1; -; mRNA. DR EMBL; BC137400; AAI37401.1; -; mRNA. DR CCDS; CCDS12151.1; -. DR PIR; T47159; T47159. DR RefSeq; NP_004549.1; NM_004558.4. DR RefSeq; XP_011526343.1; XM_011528041.2. DR PDB; 5MR4; X-ray; 2.40 A; A/B=96-197. DR PDB; 5MR5; X-ray; 2.00 A; A/B=96-197. DR PDB; 5MR9; X-ray; 2.40 A; A/B=96-197. DR PDB; 5NMZ; X-ray; 1.60 A; A/B/C/D=97-197. DR PDB; 6GL7; EM; 6.30 A; A/B=96-197. DR PDB; 6Q2O; EM; 3.65 A; A/B=96-197. DR PDB; 6Q2R; EM; 4.30 A; A/B/U/V=96-197. DR PDBsum; 5MR4; -. DR PDBsum; 5MR5; -. DR PDBsum; 5MR9; -. DR PDBsum; 5NMZ; -. DR PDBsum; 6GL7; -. DR PDBsum; 6Q2O; -. DR PDBsum; 6Q2R; -. DR AlphaFoldDB; Q99748; -. DR SMR; Q99748; -. DR BioGRID; 110958; 3. DR STRING; 9606.ENSP00000302648; -. DR PhosphoSitePlus; Q99748; -. DR BioMuta; NRTN; -. DR DMDM; 2501180; -. DR MassIVE; Q99748; -. DR PaxDb; 9606-ENSP00000302648; -. DR Antibodypedia; 11762; 503 antibodies from 40 providers. DR DNASU; 4902; -. DR Ensembl; ENST00000303212.3; ENSP00000302648.1; ENSG00000171119.3. DR GeneID; 4902; -. DR KEGG; hsa:4902; -. DR MANE-Select; ENST00000303212.3; ENSP00000302648.1; NM_004558.5; NP_004549.1. DR UCSC; uc002mde.4; human. DR AGR; HGNC:8007; -. DR CTD; 4902; -. DR DisGeNET; 4902; -. DR GeneCards; NRTN; -. DR HGNC; HGNC:8007; NRTN. DR HPA; ENSG00000171119; Tissue enhanced (heart muscle, pancreas). DR MalaCards; NRTN; -. DR MIM; 602018; gene. DR neXtProt; NX_Q99748; -. DR OpenTargets; ENSG00000171119; -. DR Orphanet; 388; Hirschsprung disease. DR PharmGKB; PA31785; -. DR VEuPathDB; HostDB:ENSG00000171119; -. DR eggNOG; ENOG502QWH4; Eukaryota. DR GeneTree; ENSGT00950000182993; -. DR HOGENOM; CLU_102221_1_1_1; -. DR InParanoid; Q99748; -. DR OMA; DITMEHM; -. DR OrthoDB; 4316464at2759; -. DR PhylomeDB; Q99748; -. DR TreeFam; TF332366; -. DR PathwayCommons; Q99748; -. 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; Q99748; -. DR SIGNOR; Q99748; -. DR BioGRID-ORCS; 4902; 7 hits in 1146 CRISPR screens. DR ChiTaRS; NRTN; human. DR GenomeRNAi; 4902; -. DR Pharos; Q99748; Tbio. DR PRO; PR:Q99748; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; Q99748; Protein. DR Bgee; ENSG00000171119; Expressed in apex of heart and 88 other cell types or tissues. DR GO; GO:0030424; C:axon; IEA:Ensembl. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IEA:Ensembl. DR GO; GO:0030116; F:glial cell-derived neurotrophic factor receptor binding; IEA:InterPro. DR GO; GO:0008083; F:growth factor activity; IDA:UniProtKB. DR GO; GO:1904399; F:heparan sulfate binding; 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:0007169; P:cell surface receptor protein tyrosine kinase signaling pathway; TAS:ProtInc. DR GO; GO:0035860; P:glial cell-derived neurotrophic factor receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0000165; P:MAPK cascade; TAS:ProtInc. DR GO; GO:0021675; P:nerve development; IEA:Ensembl. DR GO; GO:0007399; P:nervous system development; TAS:ProtInc. DR GO; GO:0001755; P:neural crest cell migration; IDA:MGI. DR GO; GO:0031175; P:neuron projection development; IDA:MGI. DR CDD; cd19383; TGF_beta_Neurturin; 1. DR Gene3D; 2.10.90.10; Cystine-knot cytokines; 1. DR InterPro; IPR029034; Cystine-knot_cytokine. DR InterPro; IPR043401; GDNF_fam. DR InterPro; IPR001839; TGF-b_C. DR PANTHER; PTHR12173; GDNF SUBFAMILY OF TGF-BETA FAMILY; 1. DR PANTHER; PTHR12173:SF3; NEURTURIN; 1. DR Pfam; PF00019; TGF_beta; 1. DR SUPFAM; SSF57501; Cystine-knot cytokines; 1. DR PROSITE; PS51362; TGF_BETA_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Disease variant; Disulfide bond; Growth factor; KW Hirschsprung disease; Reference proteome; Secreted; Signal. FT SIGNAL 1..19 FT /evidence="ECO:0000255" FT PROPEP 20..95 FT /evidence="ECO:0000250|UniProtKB:P97463" FT /id="PRO_0000034010" FT CHAIN 96..197 FT /note="Neurturin" FT /id="PRO_0000034011" FT REGION 74..93 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 149 FT /ligand="heparan sulfate group" FT /ligand_id="ChEBI:CHEBI:157750" FT /evidence="ECO:0000269|PubMed:29414779" FT BINDING 158 FT /ligand="heparan sulfate group" FT /ligand_id="ChEBI:CHEBI:157750" FT /evidence="ECO:0000269|PubMed:29414779" FT BINDING 160 FT /ligand="heparan sulfate group" FT /ligand_id="ChEBI:CHEBI:157750" FT /evidence="ECO:0000269|PubMed:29414779" FT BINDING 162 FT /ligand="heparan sulfate group" FT /ligand_id="ChEBI:CHEBI:157750" FT /evidence="ECO:0000269|PubMed:29414779" FT DISULFID 103..165 FT /evidence="ECO:0000269|PubMed:29414779, FT ECO:0000269|PubMed:31535977, ECO:0007744|PDB:5MR4, FT ECO:0007744|PDB:5MR5, ECO:0007744|PDB:5MR9, FT ECO:0007744|PDB:5NMZ, ECO:0007744|PDB:6GL7, FT ECO:0007744|PDB:6Q2O, ECO:0007744|PDB:6Q2R" FT DISULFID 130..194 FT /evidence="ECO:0000269|PubMed:29414779, FT ECO:0000269|PubMed:31535977, ECO:0007744|PDB:5MR4, FT ECO:0007744|PDB:5MR5, ECO:0007744|PDB:5MR9, FT ECO:0007744|PDB:5NMZ, ECO:0007744|PDB:6GL7, FT ECO:0007744|PDB:6Q2O, ECO:0007744|PDB:6Q2R" FT DISULFID 134..196 FT /evidence="ECO:0000269|PubMed:29414779, FT ECO:0000269|PubMed:31535977, ECO:0007744|PDB:5MR4, FT ECO:0007744|PDB:5MR5, ECO:0007744|PDB:5MR9, FT ECO:0007744|PDB:5NMZ, ECO:0007744|PDB:6GL7, FT ECO:0007744|PDB:6Q2O, ECO:0007744|PDB:6Q2R" FT DISULFID 164 FT /note="Interchain" FT /evidence="ECO:0000269|PubMed:29414779, FT ECO:0000269|PubMed:31535977, ECO:0007744|PDB:5MR4, FT ECO:0007744|PDB:5MR5, ECO:0007744|PDB:5NMZ, FT ECO:0007744|PDB:6GL7, ECO:0007744|PDB:6Q2O, FT ECO:0007744|PDB:6Q2R" FT VARIANT 96 FT /note="A -> S (may contribute to Hirschsprung disease in FT patients carrying a RET mutation; dbSNP:rs575363266)" FT /evidence="ECO:0000269|PubMed:9700200" FT /id="VAR_009498" FT MUTAGEN 158..162 FT /note="RVRAQ->AVAAA: Strongly decreased binding to heparan FT sulfate." FT /evidence="ECO:0000269|PubMed:29414779" FT STRAND 102..111 FT /evidence="ECO:0007829|PDB:5NMZ" FT HELIX 112..115 FT /evidence="ECO:0007829|PDB:5NMZ" FT STRAND 117..119 FT /evidence="ECO:0007829|PDB:5NMZ" FT STRAND 124..133 FT /evidence="ECO:0007829|PDB:5NMZ" FT HELIX 140..150 FT /evidence="ECO:0007829|PDB:5NMZ" FT STRAND 165..170 FT /evidence="ECO:0007829|PDB:5NMZ" FT STRAND 172..177 FT /evidence="ECO:0007829|PDB:5NMZ" FT STRAND 183..188 FT /evidence="ECO:0007829|PDB:5NMZ" FT STRAND 190..196 FT /evidence="ECO:0007829|PDB:5NMZ" SQ SEQUENCE 197 AA; 22405 MW; 91AFAC8C3F8971FD CRC64; MQRWKAAALA SVLCSSVLSI WMCREGLLLS HRLGPALVPL HRLPRTLDAR IARLAQYRAL LQGAPDAMEL RELTPWAGRP PGPRRRAGPR RRRARARLGA RPCGLRELEV RVSELGLGYA SDETVLFRYC AGACEAAARV YDLGLRRLRQ RRRLRRERVR AQPCCRPTAY EDEVSFLDAH SRYHTVHELS ARECACV //