NTF4_HUMAN
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 03-AUG-2022, entry version 193.
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 GlyGen; P34130; 1 site.
DR iPTMnet; P34130; -.
DR PhosphoSitePlus; P34130; -.
DR BioMuta; NTF4; -.
DR PaxDb; P34130; -.
DR PeptideAtlas; P34130; -.
DR PRIDE; P34130; -.
DR Antibodypedia; 65111; 635 antibodies from 43 providers.
DR DNASU; 4909; -.
DR Ensembl; ENST00000593537.1; ENSP00000469455.1; ENSG00000225950.8.
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 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; WISECKA; -.
DR OrthoDB; 1156054at2759; -.
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 1067 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 skeletal muscle tissue and 67 other tissues.
DR ExpressionAtlas; P34130; baseline and differential.
DR Genevisible; P34130; HS.
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; -; 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; PTHR11589; 1.
DR PANTHER; PTHR11589:SF8; PTHR11589:SF8; 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; SSF57501; 1.
DR PROSITE; PS00248; NGF_1; 1.
DR PROSITE; PS50270; NGF_2; 1.
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; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:19765683"
FT /id="VAR_063196"
FT VARIANT 84
FT /note="E -> K (in GLC1O; unknown pathological 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; unknown pathological 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; unknown pathological significance;
FT dbSNP:rs121918428)"
FT /evidence="ECO:0000269|PubMed:19765683"
FT /id="VAR_063205"
FT VARIANT 206
FT /note="R -> W (in GLC1O; also found in patients with normal
FT pressure glaucoma; unknown pathological significance;
FT impaired ligand-mediated TRKB signaling and reduced neurite
FT outgrowth; 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; unknown pathological 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
