ID SYT4_HUMAN Reviewed; 425 AA. AC Q9H2B2; B4DEU3; Q9P2K4; DT 18-OCT-2001, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2001, sequence version 1. DT 27-MAR-2024, entry version 190. DE RecName: Full=Synaptotagmin-4; DE AltName: Full=Synaptotagmin IV; DE Short=SytIV; GN Name=SYT4; Synonyms=KIAA1342; 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] (ISOFORM 1). RX PubMed=10938284; DOI=10.1074/jbc.m005801200; RA Ferguson G.D., Chen X.-N., Korenberg J.R., Herschman H.R.; RT "The human synaptotagmin IV gene defines an evolutionary break point RT between syntenic mouse and human chromosome regions but retains ligand RT inducibility and tissue specificity."; RL J. Biol. Chem. 275:36920-36926(2000). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=10718198; DOI=10.1093/dnares/7.1.65; RA Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. XVI. The RT complete sequences of 150 new cDNA clones from brain which code for large RT proteins in vitro."; RL DNA Res. 7:65-73(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Cerebellum; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16177791; DOI=10.1038/nature03983; RA Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D., RA Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., RA Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J., RA Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L., RA Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., RA Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., RA Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K., RA Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R., RA Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.; RT "DNA sequence and analysis of human chromosome 18."; RL Nature 437:551-555(2005). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; 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 FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=23999003; DOI=10.1016/j.jdermsci.2013.07.010; RA Yoo J.C., Lim T.Y., Park J.S., Hah Y.S., Park N., Hong S.G., Park J.Y., RA Yoon T.J.; RT "SYT14L, especially its C2 domain, is involved in regulating melanocyte RT differentiation."; RL J. Dermatol. Sci. 72:246-251(2013). RN [7] RP STRUCTURE BY NMR OF 154-278. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the first C2 domain of synaptotagmin IV from human RT fetal brain (KIAA1342)."; RL Submitted (DEC-2003) to the PDB data bank. CC -!- FUNCTION: Synaptotagmin family member which does not bind Ca(2+) CC (PubMed:23999003) (By similarity). Involved in neuronal dense core CC vesicles (DCVs) mobility through its interaction with KIF1A. Upon CC increased neuronal activity, phosphorylation by MAPK8/JNK1 destabilizes CC the interaction with KIF1A and captures DCVs to synapses (By CC similarity). Plays a role in dendrite formation by melanocytes CC (PubMed:23999003). {ECO:0000250|UniProtKB:P50232, CC ECO:0000269|PubMed:23999003}. CC -!- COFACTOR: CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000255|PROSITE- CC ProRule:PRU00041}; CC -!- SUBUNIT: Interacts with KIF1A; the interaction increases in presence of CC calcium and decreases when SYT4 is phosphorylated at Ser-135. CC {ECO:0000250|UniProtKB:P50232}. CC -!- INTERACTION: CC Q9H2B2; Q14596: NBR1; NbExp=3; IntAct=EBI-751132, EBI-742698; CC Q9H2B2; Q14596-2: NBR1; NbExp=3; IntAct=EBI-751132, EBI-11081753; CC Q9H2B2; Q9UI09: NDUFA12; NbExp=3; IntAct=EBI-751132, EBI-1246332; CC Q9H2B2; O43765: SGTA; NbExp=7; IntAct=EBI-751132, EBI-347996; CC Q9H2B2; Q96EQ0: SGTB; NbExp=3; IntAct=EBI-751132, EBI-744081; CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, secretory vesicle, neuronal CC dense core vesicle membrane {ECO:0000250|UniProtKB:P50232}; Single-pass CC membrane protein {ECO:0000250|UniProtKB:P50232}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9H2B2-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9H2B2-2; Sequence=VSP_056643; CC -!- TISSUE SPECIFICITY: Expressed in melanocytes (PubMed:23999003). CC Expressed in brain. Within brain, expression is highest in hippocampus, CC with substantial levels also detected in amygdala and thalamus CC (PubMed:23999003). {ECO:0000269|PubMed:23999003}. CC -!- DOMAIN: Unlike in other synaptotagmin family members, the first C2 CC domain/C2A does not bind Ca(2+) neither mediates Ca(2+)-dependent CC phospholipid binding. An aspartate-to-serine substitution in this CC domain inactivates Ca(2+)/phospho-lipid binding. CC {ECO:0000250|UniProtKB:P50232}. CC -!- PTM: Phosphorylation at Ser-135 by MAPK8/JNK1 reduces interaction with CC KIF1A and neuronal dense core vesicles mobility. CC {ECO:0000250|UniProtKB:P50232}. CC -!- SIMILARITY: Belongs to the synaptotagmin family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA92580.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={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; AF299075; AAG37229.1; -; mRNA. DR EMBL; AB037763; BAA92580.1; ALT_INIT; mRNA. DR EMBL; AK293791; BAG57204.1; -; mRNA. DR EMBL; AC091039; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC036538; AAH36538.1; -; mRNA. DR CCDS; CCDS11922.1; -. [Q9H2B2-1] DR RefSeq; NP_065834.1; NM_020783.3. [Q9H2B2-1] DR PDB; 1UGK; NMR; -; A=154-278. DR PDBsum; 1UGK; -. DR AlphaFoldDB; Q9H2B2; -. DR SMR; Q9H2B2; -. DR BioGRID; 112724; 8. DR ELM; Q9H2B2; -. DR IntAct; Q9H2B2; 7. DR MINT; Q9H2B2; -. DR STRING; 9606.ENSP00000255224; -. DR GlyConnect; 2930; 1 O-Linked glycan (1 site). DR iPTMnet; Q9H2B2; -. DR PhosphoSitePlus; Q9H2B2; -. DR SwissPalm; Q9H2B2; -. DR BioMuta; SYT4; -. DR DMDM; 18202937; -. DR MassIVE; Q9H2B2; -. DR PaxDb; 9606-ENSP00000255224; -. DR PeptideAtlas; Q9H2B2; -. DR ProteomicsDB; 80522; -. [Q9H2B2-1] DR Antibodypedia; 22400; 447 antibodies from 30 providers. DR DNASU; 6860; -. DR Ensembl; ENST00000255224.8; ENSP00000255224.2; ENSG00000132872.12. [Q9H2B2-1] DR Ensembl; ENST00000590752.5; ENSP00000466930.1; ENSG00000132872.12. [Q9H2B2-2] DR GeneID; 6860; -. DR KEGG; hsa:6860; -. DR MANE-Select; ENST00000255224.8; ENSP00000255224.2; NM_020783.4; NP_065834.1. DR UCSC; uc002law.4; human. [Q9H2B2-1] DR AGR; HGNC:11512; -. DR CTD; 6860; -. DR DisGeNET; 6860; -. DR GeneCards; SYT4; -. DR HGNC; HGNC:11512; SYT4. DR HPA; ENSG00000132872; Tissue enriched (brain). DR MIM; 600103; gene. DR neXtProt; NX_Q9H2B2; -. DR OpenTargets; ENSG00000132872; -. DR PharmGKB; PA36293; -. DR VEuPathDB; HostDB:ENSG00000132872; -. DR eggNOG; KOG1028; Eukaryota. DR GeneTree; ENSGT00940000159026; -. DR HOGENOM; CLU_023008_7_3_1; -. DR InParanoid; Q9H2B2; -. DR OMA; FMVNIKE; -. DR OrthoDB; 590187at2759; -. DR PhylomeDB; Q9H2B2; -. DR TreeFam; TF315600; -. DR PathwayCommons; Q9H2B2; -. DR SignaLink; Q9H2B2; -. DR SIGNOR; Q9H2B2; -. DR BioGRID-ORCS; 6860; 14 hits in 1146 CRISPR screens. DR ChiTaRS; SYT4; human. DR EvolutionaryTrace; Q9H2B2; -. DR GeneWiki; SYT4; -. DR GenomeRNAi; 6860; -. DR Pharos; Q9H2B2; Tbio. DR PRO; PR:Q9H2B2; -. DR Proteomes; UP000005640; Chromosome 18. DR RNAct; Q9H2B2; Protein. DR Bgee; ENSG00000132872; Expressed in cerebellar vermis and 129 other cell types or tissues. DR ExpressionAtlas; Q9H2B2; baseline and differential. DR GO; GO:0097449; C:astrocyte projection; IEA:Ensembl. DR GO; GO:0030424; C:axon; IBA:GO_Central. DR GO; GO:0030425; C:dendrite; IEA:Ensembl. DR GO; GO:0032127; C:dense core granule membrane; NAS:ParkinsonsUK-UCL. DR GO; GO:0070382; C:exocytic vesicle; IBA:GO_Central. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0000139; C:Golgi membrane; NAS:ParkinsonsUK-UCL. DR GO; GO:1990742; C:microvesicle; IEA:Ensembl. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0098992; C:neuronal dense core vesicle; ISS:UniProtKB. DR GO; GO:0099012; C:neuronal dense core vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0045202; C:synapse; IBA:GO_Central. DR GO; GO:0030672; C:synaptic vesicle membrane; NAS:ParkinsonsUK-UCL. DR GO; GO:0005509; F:calcium ion binding; IBA:GO_Central. DR GO; GO:0005544; F:calcium-dependent phospholipid binding; IBA:GO_Central. DR GO; GO:0030276; F:clathrin binding; IBA:GO_Central. DR GO; GO:0001786; F:phosphatidylserine binding; IBA:GO_Central. DR GO; GO:0000149; F:SNARE binding; IBA:GO_Central. DR GO; GO:0048791; P:calcium ion-regulated exocytosis of neurotransmitter; IBA:GO_Central. DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW. DR GO; GO:0071277; P:cellular response to calcium ion; IBA:GO_Central. DR GO; GO:0099519; P:dense core granule cytoskeletal transport; ISS:UniProtKB. DR GO; GO:0007613; P:memory; IEA:Ensembl. DR GO; GO:0045955; P:negative regulation of calcium ion-dependent exocytosis; NAS:ParkinsonsUK-UCL. DR GO; GO:0033604; P:negative regulation of catecholamine secretion; IGI:ParkinsonsUK-UCL. DR GO; GO:0050709; P:negative regulation of protein secretion; IEA:Ensembl. DR GO; GO:1905433; P:negative regulation of retrograde trans-synaptic signaling by neuropeptide; IEA:Ensembl. DR GO; GO:0048174; P:negative regulation of short-term neuronal synaptic plasticity; IEA:Ensembl. DR GO; GO:2000301; P:negative regulation of synaptic vesicle exocytosis; IEA:Ensembl. DR GO; GO:0045956; P:positive regulation of calcium ion-dependent exocytosis; NAS:ParkinsonsUK-UCL. DR GO; GO:1903861; P:positive regulation of dendrite extension; IDA:UniProtKB. DR GO; GO:1905415; P:positive regulation of dense core granule exocytosis; IEA:Ensembl. DR GO; GO:0014049; P:positive regulation of glutamate secretion; IEA:Ensembl. DR GO; GO:0017158; P:regulation of calcium ion-dependent exocytosis; IBA:GO_Central. DR GO; GO:0014059; P:regulation of dopamine secretion; IBA:GO_Central. DR GO; GO:0030100; P:regulation of endocytosis; IEA:Ensembl. DR GO; GO:0150044; P:regulation of postsynaptic dense core vesicle exocytosis; IEA:Ensembl. DR GO; GO:0150035; P:regulation of trans-synaptic signaling by BDNF, modulating synaptic transmission; IEA:Ensembl. DR GO; GO:0031338; P:regulation of vesicle fusion; IEA:Ensembl. DR GO; GO:0006906; P:vesicle fusion; IBA:GO_Central. DR CDD; cd08388; C2A_Synaptotagmin-4-11; 1. DR CDD; cd08404; C2B_Synaptotagmin-4; 1. DR Gene3D; 2.60.40.150; C2 domain; 2. DR InterPro; IPR000008; C2_dom. DR InterPro; IPR035892; C2_domain_sf. DR InterPro; IPR001565; Synaptotagmin. DR PANTHER; PTHR10024; SYNAPTOTAGMIN; 1. DR PANTHER; PTHR10024:SF114; SYNAPTOTAGMIN-4; 1. DR Pfam; PF00168; C2; 2. DR PRINTS; PR00399; SYNAPTOTAGMN. DR SMART; SM00239; C2; 2. DR SUPFAM; SSF49562; C2 domain (Calcium/lipid-binding domain, CaLB); 2. DR PROSITE; PS50004; C2; 2. DR Genevisible; Q9H2B2; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Calcium; Cytoplasmic vesicle; KW Differentiation; Membrane; Metal-binding; Phosphoprotein; KW Reference proteome; Repeat; Transmembrane; Transmembrane helix. FT CHAIN 1..425 FT /note="Synaptotagmin-4" FT /id="PRO_0000183948" FT TOPO_DOM 1..16 FT /note="Vesicular" FT /evidence="ECO:0000255" FT TRANSMEM 17..37 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 38..425 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 153..274 FT /note="C2 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT DOMAIN 287..420 FT /note="C2 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT REGION 73..93 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 127..147 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 246 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT BINDING 249 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT BINDING 252 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT MOD_RES 135 FT /note="Phosphoserine; by MAPK8" FT /evidence="ECO:0000250|UniProtKB:P40749" FT VAR_SEQ 12..29 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_056643" FT VARIANT 142 FT /note="S -> N (in dbSNP:rs16977447)" FT /id="VAR_052239" FT STRAND 156..164 FT /evidence="ECO:0007829|PDB:1UGK" FT HELIX 165..167 FT /evidence="ECO:0007829|PDB:1UGK" FT STRAND 169..179 FT /evidence="ECO:0007829|PDB:1UGK" FT TURN 185..188 FT /evidence="ECO:0007829|PDB:1UGK" FT STRAND 191..199 FT /evidence="ECO:0007829|PDB:1UGK" FT TURN 200..202 FT /evidence="ECO:0007829|PDB:1UGK" FT STRAND 204..207 FT /evidence="ECO:0007829|PDB:1UGK" FT STRAND 218..226 FT /evidence="ECO:0007829|PDB:1UGK" FT HELIX 233..235 FT /evidence="ECO:0007829|PDB:1UGK" FT STRAND 237..245 FT /evidence="ECO:0007829|PDB:1UGK" FT STRAND 255..260 FT /evidence="ECO:0007829|PDB:1UGK" FT STRAND 271..276 FT /evidence="ECO:0007829|PDB:1UGK" SQ SEQUENCE 425 AA; 47958 MW; DA3D4CB175CB528D CRC64; MAPITTSREE FDEIPTVVGI FSAFGLVFTV SLFAWICCQR KSSKSNKTPP YKFVHVLKGV DIYPENLNSK KKFGADDKNE VKNKPAVPKN SLHLDLEKRD LNGNFPKTNL KPGSPSDLEN ATPKLFLEGE KESVSPESLK SSTSLTSEEK QEKLGTLFFS LEYNFERKAF VVNIKEARGL PAMDEQSMTS DPYIKMTILP EKKHKVKTRV LRKTLDPAFD ETFTFYGIPY TQIQELALHF TILSFDRFSR DDIIGEVLIP LSGIELSEGK MLMNREIIKR NVRKSSGRGE LLISLCYQST TNTLTVVVLK ARHLPKSDVS GLSDPYVKVN LYHAKKRISK KKTHVKKCTP NAVFNELFVF DIPCEGLEDI SVEFLVLDSE RGSRNEVIGQ LVLGAAAEGT GGEHWKEICD YPRRQIAKWH VLCDG //