ID   NTF4_HUMAN              Reviewed;         210 AA.
AC   P34130; Q6FH56;
DT   01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT   01-FEB-1994, sequence version 1.
DT   24-JAN-2024, entry version 201.
DE   RecName: Full=Neurotrophin-4;
DE            Short=NT-4;
DE   AltName: Full=Neurotrophin-5;
DE            Short=NT-5;
DE   AltName: Full=Neutrophic factor 4;
DE   Flags: Precursor;
GN   Name=NTF4; Synonyms=NTF5;
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].
RX   PubMed=1742028; DOI=10.1016/0896-6273(91)90287-a;
RA   Berkemeier L.R., Winslow J.W., Kaplan D.R., Nikolics K., Goeddel D.V.,
RA   Rosenthal A.;
RT   "Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB.";
RL   Neuron 7:857-866(1991).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   TISSUE=Prostate;
RX   PubMed=1313578; DOI=10.1073/pnas.89.7.3060;
RA   Ip N.Y., Ibanez C.F., Nye S.H., McClain J., Jones P.F., Gies D.R.,
RA   Belluscio L., le Beau M.M., Espinosa R. III, Squinto S.P., Persson H.,
RA   Yancopoulos G.D.;
RT   "Mammalian neurotrophin-4: structure, chromosomal localization, tissue
RT   distribution, and receptor specificity.";
RL   Proc. Natl. Acad. Sci. U.S.A. 89:3060-3064(1992).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 MRNA].
RC   TISSUE=Ovary;
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   [6]
RP   X-RAY CRYSTALLOGRAPHY (2.75 ANGSTROMS).
RX   PubMed=10631974; DOI=10.1110/ps.8.12.2589;
RA   Robinson R.C., Radziejewski C., Spraggon G., Greenwald J., Kostura M.R.,
RA   Burtnick L.D., Stuart D.I., Choe S., Jones E.Y.;
RT   "The structures of the neurotrophin 4 homodimer and the brain-derived
RT   neurotrophic factor/neurotrophin 4 heterodimer reveal a common Trk-binding
RT   site.";
RL   Protein Sci. 8:2589-2597(1999).
RN   [7]
RP   INVOLVEMENT IN SUSCEPTIBILITY TO GLAUCOMA, VARIANTS GLC1O TYR-7; LYS-84;
RP   HIS-90; TRP-206; GLN-206 AND GLY-209, VARIANTS VAL-88 AND SER-207, AND
RP   CHARACTERIZATION OF VARIANT GLC1O TRP-206.
RX   PubMed=19765683; DOI=10.1016/j.ajhg.2009.08.016;
RA   Pasutto F., Matsumoto T., Mardin C.Y., Sticht H., Brandstatter J.H.,
RA   Michels-Rautenstrauss K., Weisschuh N., Gramer E., Ramdas W.D.,
RA   van Koolwijk L.M., Klaver C.C., Vingerling J.R., Weber B.H., Kruse F.E.,
RA   Rautenstrauss B., Barde Y.A., Reis A.;
RT   "Heterozygous NTF4 mutations impairing neurotrophin-4 signaling in patients
RT   with primary open-angle glaucoma.";
RL   Am. J. Hum. Genet. 85:447-456(2009).
RN   [8]
RP   VARIANTS VAL-88; ASN-89; CYS-90; GLY-114; HIS-133; CYS-140; TRP-206 AND
RP   ILE-207, AND DISCUSSION OF ASSOCIATION WITH GLAUCOMA.
RX   PubMed=20215012; DOI=10.1016/j.ajhg.2009.11.018;
RA   Liu Y., Liu W., Crooks K., Schmidt S., Allingham R.R., Hauser M.A.;
RT   "No evidence of association of heterozygous NTF4 mutations in patients with
RT   primary open-angle glaucoma.";
RL   Am. J. Hum. Genet. 86:498-499(2010).
CC   -!- FUNCTION: Target-derived survival factor for peripheral sensory
CC       sympathetic neurons.
CC   -!- INTERACTION:
CC       P34130; Q6UY14-3: ADAMTSL4; NbExp=3; IntAct=EBI-3907456, EBI-10173507;
CC       P34130; P23560: BDNF; NbExp=6; IntAct=EBI-3907456, EBI-1026003;
CC       P34130; O43186: CRX; NbExp=3; IntAct=EBI-3907456, EBI-748171;
CC       P34130; O76003: GLRX3; NbExp=3; IntAct=EBI-3907456, EBI-374781;
CC   -!- SUBCELLULAR LOCATION: Secreted.
CC   -!- TISSUE SPECIFICITY: Highest levels in prostate, lower levels in thymus,
CC       placenta, and skeletal muscle. Expressed in embryonic and adult
CC       tissues.
CC   -!- DISEASE: Glaucoma 1, open angle, O (GLC1O) [MIM:613100]: A form of
CC       primary open angle glaucoma (POAG). POAG is characterized by a specific
CC       pattern of optic nerve and visual field defects. The angle of the
CC       anterior chamber of the eye is open, and usually the intraocular
CC       pressure is increased. However, glaucoma can occur at any intraocular
CC       pressure. The disease is generally asymptomatic until the late stages,
CC       by which time significant and irreversible optic nerve damage has
CC       already taken place. {ECO:0000269|PubMed:19765683,
CC       ECO:0000269|PubMed:20215012}. Note=Disease susceptibility may be
CC       associated with variants affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the NGF-beta family. {ECO:0000305}.
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DR   EMBL; M86528; AAA60154.1; -; Genomic_DNA.
DR   EMBL; BT019368; AAV38175.1; -; mRNA.
DR   EMBL; BT019369; AAV38176.1; -; mRNA.
DR   EMBL; CR541900; CAG46698.1; -; mRNA.
DR   EMBL; BC012421; AAH12421.1; -; mRNA.
DR   CCDS; CCDS12754.1; -.
DR   PIR; A42687; A42687.
DR   RefSeq; NP_006170.1; NM_006179.4.
DR   RefSeq; XP_005259019.1; XM_005258962.3.
DR   RefSeq; XP_006723295.1; XM_006723232.3.
DR   RefSeq; XP_011525311.1; XM_011527009.2.
DR   RefSeq; XP_011525312.1; XM_011527010.2.
DR   PDB; 1B8M; X-ray; 2.75 A; B=81-210.
DR   PDB; 1B98; X-ray; 2.75 A; A/M=81-210.
DR   PDB; 1HCF; X-ray; 2.70 A; A/B=81-210.
DR   PDBsum; 1B8M; -.
DR   PDBsum; 1B98; -.
DR   PDBsum; 1HCF; -.
DR   AlphaFoldDB; P34130; -.
DR   SMR; P34130; -.
DR   BioGRID; 110964; 15.
DR   CORUM; P34130; -.
DR   IntAct; P34130; 7.
DR   STRING; 9606.ENSP00000469455; -.
DR   GlyCosmos; P34130; 1 site, No reported glycans.
DR   GlyGen; P34130; 1 site.
DR   iPTMnet; P34130; -.
DR   PhosphoSitePlus; P34130; -.
DR   BioMuta; NTF4; -.
DR   PaxDb; 9606-ENSP00000469455; -.
DR   PeptideAtlas; P34130; -.
DR   Antibodypedia; 65111; 705 antibodies from 43 providers.
DR   DNASU; 4909; -.
DR   Ensembl; ENST00000593537.2; ENSP00000469455.1; ENSG00000225950.9.
DR   Ensembl; ENST00000594938.2; ENSP00000512387.1; ENSG00000225950.9.
DR   Ensembl; ENST00000595857.6; ENSP00000471508.2; ENSG00000225950.9.
DR   Ensembl; ENST00000696088.1; ENSP00000512384.1; ENSG00000225950.9.
DR   Ensembl; ENST00000696089.1; ENSP00000512385.1; ENSG00000225950.9.
DR   Ensembl; ENST00000696090.1; ENSP00000512386.1; ENSG00000225950.9.
DR   Ensembl; ENST00000696091.1; ENSP00000512388.1; ENSG00000225950.9.
DR   GeneID; 4909; -.
DR   KEGG; hsa:4909; -.
DR   MANE-Select; ENST00000593537.2; ENSP00000469455.1; NM_006179.5; NP_006170.1.
DR   UCSC; uc061ayz.1; human.
DR   AGR; HGNC:8024; -.
DR   CTD; 4909; -.
DR   DisGeNET; 4909; -.
DR   GeneCards; NTF4; -.
DR   HGNC; HGNC:8024; NTF4.
DR   HPA; ENSG00000225950; Tissue enhanced (prostate, skeletal muscle, skin).
DR   MalaCards; NTF4; -.
DR   MIM; 162662; gene.
DR   MIM; 613100; phenotype.
DR   neXtProt; NX_P34130; -.
DR   OpenTargets; ENSG00000225950; -.
DR   Orphanet; 353225; NON RARE IN EUROPE: Primary adult open-angle glaucoma.
DR   PharmGKB; PA162398206; -.
DR   VEuPathDB; HostDB:ENSG00000225950; -.
DR   eggNOG; ENOG502R4FK; Eukaryota.
DR   GeneTree; ENSGT00390000007725; -.
DR   HOGENOM; CLU_059942_2_1_1; -.
DR   InParanoid; P34130; -.
DR   OMA; HWISECK; -.
DR   OrthoDB; 5399313at2759; -.
DR   PhylomeDB; P34130; -.
DR   TreeFam; TF106463; -.
DR   PathwayCommons; P34130; -.
DR   Reactome; R-HSA-9026357; NTF4 activates NTRK2 (TRKB) signaling.
DR   Reactome; R-HSA-9026519; Activated NTRK2 signals through RAS.
DR   Reactome; R-HSA-9026527; Activated NTRK2 signals through PLCG1.
DR   Reactome; R-HSA-9028335; Activated NTRK2 signals through PI3K.
DR   Reactome; R-HSA-9028731; Activated NTRK2 signals through FRS2 and FRS3.
DR   SignaLink; P34130; -.
DR   SIGNOR; P34130; -.
DR   BioGRID-ORCS; 4909; 23 hits in 1145 CRISPR screens.
DR   EvolutionaryTrace; P34130; -.
DR   GenomeRNAi; 4909; -.
DR   Pharos; P34130; Tbio.
DR   PRO; PR:P34130; -.
DR   Proteomes; UP000005640; Chromosome 19.
DR   RNAct; P34130; Protein.
DR   Bgee; ENSG00000225950; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 69 other cell types or tissues.
DR   ExpressionAtlas; P34130; baseline and differential.
DR   GO; GO:0030424; C:axon; IBA:GO_Central.
DR   GO; GO:0030425; C:dendrite; IBA:GO_Central.
DR   GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR   GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR   GO; GO:0008021; C:synaptic vesicle; IBA:GO_Central.
DR   GO; GO:0008083; F:growth factor activity; IBA:GO_Central.
DR   GO; GO:0005163; F:nerve growth factor receptor binding; IBA:GO_Central.
DR   GO; GO:0008344; P:adult locomotory behavior; ISS:UniProtKB.
DR   GO; GO:0008544; P:epidermis development; ISS:UniProtKB.
DR   GO; GO:0007402; P:ganglion mother cell fate determination; ISS:UniProtKB.
DR   GO; GO:0060384; P:innervation; IEA:Ensembl.
DR   GO; GO:0007616; P:long-term memory; ISS:UniProtKB.
DR   GO; GO:0042490; P:mechanoreceptor differentiation; IEA:Ensembl.
DR   GO; GO:0007613; P:memory; IBA:GO_Central.
DR   GO; GO:0050804; P:modulation of chemical synaptic transmission; IBA:GO_Central.
DR   GO; GO:0043524; P:negative regulation of neuron apoptotic process; IBA:GO_Central.
DR   GO; GO:0021675; P:nerve development; IBA:GO_Central.
DR   GO; GO:0038180; P:nerve growth factor signaling pathway; IBA:GO_Central.
DR   GO; GO:0048812; P:neuron projection morphogenesis; IBA:GO_Central.
DR   GO; GO:0007422; P:peripheral nervous system development; IBA:GO_Central.
DR   GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IBA:GO_Central.
DR   GO; GO:0045664; P:regulation of neuron differentiation; IBA:GO_Central.
DR   GO; GO:0008052; P:sensory organ boundary specification; ISS:UniProtKB.
DR   GO; GO:0061193; P:taste bud development; IEA:Ensembl.
DR   GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR   Gene3D; 2.10.90.10; Cystine-knot cytokines; 1.
DR   InterPro; IPR029034; Cystine-knot_cytokine.
DR   InterPro; IPR020408; Nerve_growth_factor-like.
DR   InterPro; IPR002072; Nerve_growth_factor-rel.
DR   InterPro; IPR019846; Nerve_growth_factor_CS.
DR   InterPro; IPR020432; Neurotrophin-4.
DR   PANTHER; PTHR11589; NERVE GROWTH FACTOR NGF -RELATED; 1.
DR   PANTHER; PTHR11589:SF8; NEUROTROPHIN-4; 1.
DR   Pfam; PF00243; NGF; 1.
DR   PIRSF; PIRSF001789; NGF; 1.
DR   PRINTS; PR01915; NEUROTROPHN4.
DR   PRINTS; PR00268; NGF.
DR   SMART; SM00140; NGF; 1.
DR   SUPFAM; SSF57501; Cystine-knot cytokines; 1.
DR   PROSITE; PS00248; NGF_1; 1.
DR   PROSITE; PS50270; NGF_2; 1.
DR   Genevisible; P34130; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Cleavage on pair of basic residues; Disulfide bond; Glaucoma;
KW   Glycoprotein; Growth factor; Reference proteome; Secreted; Signal.
FT   SIGNAL          1..24
FT                   /evidence="ECO:0000255"
FT   PROPEP          25..80
FT                   /id="PRO_0000019669"
FT   CHAIN           81..210
FT                   /note="Neurotrophin-4"
FT                   /id="PRO_0000019670"
FT   CARBOHYD        76
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        97..170
FT   DISULFID        141..199
FT   DISULFID        158..201
FT   VARIANT         7
FT                   /note="C -> Y (in GLC1O; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:19765683"
FT                   /id="VAR_063196"
FT   VARIANT         84
FT                   /note="E -> K (in GLC1O; uncertain significance;
FT                   dbSNP:rs756962734)"
FT                   /evidence="ECO:0000269|PubMed:19765683"
FT                   /id="VAR_063197"
FT   VARIANT         88
FT                   /note="A -> V (in dbSNP:rs61732310)"
FT                   /evidence="ECO:0000269|PubMed:19765683,
FT                   ECO:0000269|PubMed:20215012"
FT                   /id="VAR_063198"
FT   VARIANT         89
FT                   /note="S -> N (in dbSNP:rs374367338)"
FT                   /evidence="ECO:0000269|PubMed:20215012"
FT                   /id="VAR_063199"
FT   VARIANT         90
FT                   /note="R -> C (in dbSNP:rs751743400)"
FT                   /evidence="ECO:0000269|PubMed:20215012"
FT                   /id="VAR_063200"
FT   VARIANT         90
FT                   /note="R -> H (in GLC1O; uncertain significance;
FT                   dbSNP:rs766504681)"
FT                   /evidence="ECO:0000269|PubMed:19765683"
FT                   /id="VAR_063201"
FT   VARIANT         114
FT                   /note="R -> G (in dbSNP:rs377553005)"
FT                   /evidence="ECO:0000269|PubMed:20215012"
FT                   /id="VAR_063202"
FT   VARIANT         133
FT                   /note="R -> H (in dbSNP:rs977260366)"
FT                   /evidence="ECO:0000269|PubMed:20215012"
FT                   /id="VAR_063203"
FT   VARIANT         140
FT                   /note="R -> C (in dbSNP:rs201069064)"
FT                   /evidence="ECO:0000269|PubMed:20215012"
FT                   /id="VAR_063204"
FT   VARIANT         206
FT                   /note="R -> Q (in GLC1O; uncertain significance;
FT                   dbSNP:rs121918428)"
FT                   /evidence="ECO:0000269|PubMed:19765683"
FT                   /id="VAR_063205"
FT   VARIANT         206
FT                   /note="R -> W (in GLC1O; impaired ligand-mediated TRKB
FT                   signaling and reduced neurite outgrowth;
FT                   dbSNP:rs121918427)"
FT                   /evidence="ECO:0000269|PubMed:19765683,
FT                   ECO:0000269|PubMed:20215012"
FT                   /id="VAR_063206"
FT   VARIANT         207
FT                   /note="T -> I (in dbSNP:rs371861346)"
FT                   /evidence="ECO:0000269|PubMed:20215012"
FT                   /id="VAR_063207"
FT   VARIANT         207
FT                   /note="T -> S"
FT                   /evidence="ECO:0000269|PubMed:19765683"
FT                   /id="VAR_063208"
FT   VARIANT         209
FT                   /note="R -> G (in GLC1O; uncertain significance;
FT                   dbSNP:rs200675509)"
FT                   /evidence="ECO:0000269|PubMed:19765683"
FT                   /id="VAR_063209"
FT   STRAND          83..85
FT                   /evidence="ECO:0007829|PDB:1HCF"
FT   HELIX           88..90
FT                   /evidence="ECO:0007829|PDB:1HCF"
FT   STRAND          94..97
FT                   /evidence="ECO:0007829|PDB:1HCF"
FT   STRAND          99..104
FT                   /evidence="ECO:0007829|PDB:1HCF"
FT   STRAND          109..112
FT                   /evidence="ECO:0007829|PDB:1HCF"
FT   STRAND          117..120
FT                   /evidence="ECO:0007829|PDB:1HCF"
FT   STRAND          122..125
FT                   /evidence="ECO:0007829|PDB:1HCF"
FT   STRAND          127..133
FT                   /evidence="ECO:0007829|PDB:1HCF"
FT   STRAND          136..141
FT                   /evidence="ECO:0007829|PDB:1HCF"
FT   TURN            146..148
FT                   /evidence="ECO:0007829|PDB:1B98"
FT   STRAND          153..156
FT                   /evidence="ECO:0007829|PDB:1HCF"
FT   TURN            163..165
FT                   /evidence="ECO:0007829|PDB:1HCF"
FT   STRAND          166..182
FT                   /evidence="ECO:0007829|PDB:1HCF"
FT   STRAND          184..186
FT                   /evidence="ECO:0007829|PDB:1B98"
FT   STRAND          188..205
FT                   /evidence="ECO:0007829|PDB:1HCF"
SQ   SEQUENCE   210 AA;  22427 MW;  DBC6A30195E139AD CRC64;
     MLPLPSCSLP ILLLFLLPSV PIESQPPPST LPPFLAPEWD LLSPRVVLSR GAPAGPPLLF
     LLEAGAFRES AGAPANRSRR GVSETAPASR RGELAVCDAV SGWVTDRRTA VDLRGREVEV
     LGEVPAAGGS PLRQYFFETR CKADNAEEGG PGAGGGGCRG VDRRHWVSEC KAKQSYVRAL
     TADAQGRVGW RWIRIDTACV CTLLSRTGRA
//