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}.
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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
//