SYT4_RAT
ID SYT4_RAT Reviewed; 425 AA.
AC P50232;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 03-AUG-2022, entry version 161.
DE RecName: Full=Synaptotagmin-4;
DE AltName: Full=Synaptotagmin IV;
DE Short=SytIV;
GN Name=Syt4;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=7993622; DOI=10.1016/0896-6273(94)90415-4;
RA Ullrich B., Li C., Zhang J.Z., McMahon H., Anderson R.G., Geppert M.,
RA Suedhof T.C.;
RT "Functional properties of multiple synaptotagmins in brain.";
RL Neuron 13:1281-1291(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=7892240; DOI=10.1073/pnas.92.6.2164;
RA Vician L., Lim I.K., Ferguson G., Tocco G., Baudry M., Herschman H.R.;
RT "Synaptotagmin IV is an immediate early gene induced by depolarization in
RT PC12 cells and in brain.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:2164-2168(1995).
RN [3]
RP FUNCTION, DOMAIN, AND MUTAGENESIS OF SER-244.
RX PubMed=9162066; DOI=10.1074/jbc.272.22.14314;
RA von Poser C., Ichtchenko K., Shao X., Rizo J., Suedhof T.C.;
RT "The evolutionary pressure to inactivate. A subclass of synaptotagmins with
RT an amino acid substitution that abolishes Ca2+ binding.";
RL J. Biol. Chem. 272:14314-14319(1997).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-135, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [5]
RP FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF SER-135, PHOSPHORYLATION AT
RP SER-135, AND INTERACTION WITH KIF1A.
RX PubMed=29166604; DOI=10.1016/j.celrep.2017.10.084;
RA Bharat V., Siebrecht M., Burk K., Ahmed S., Reissner C.,
RA Kohansal-Nodehi M., Steubler V., Zweckstetter M., Ting J.T., Dean C.;
RT "Capture of Dense Core Vesicles at Synapses by JNK-Dependent
RT Phosphorylation of Synaptotagmin-4.";
RL Cell Rep. 21:2118-2133(2017).
RN [6]
RP INTERACTION WITH KIF1A, AND SUBCELLULAR LOCATION.
RX PubMed=30021165; DOI=10.1016/j.celrep.2018.06.071;
RA Stucchi R., Plucinska G., Hummel J.J.A., Zahavi E.E., Guerra San Juan I.,
RA Klykov O., Scheltema R.A., Altelaar A.F.M., Hoogenraad C.C.;
RT "Regulation of KIF1A-Driven Dense Core Vesicle Transport: Ca2+/CaM Controls
RT DCV Binding and Liprin-alpha/TANC2 Recruits DCVs to Postsynaptic Sites.";
RL Cell Rep. 24:685-700(2018).
CC -!- FUNCTION: Synaptotagmin family member which does not bind Ca(2+)
CC (PubMed:7993622). Involved in neuronal dense core vesicles (DCVs)
CC mobility through its interaction with KIF1A. Upon increased neuronal
CC activity, phosphorylation by MAPK8/JNK1 destabilizes the interaction
CC with KIF1A and captures DCVs to synapses (PubMed:29166604). Plays a
CC role in dendrite formation by melanocytes (By similarity).
CC {ECO:0000250|UniProtKB:Q9H2B2, ECO:0000269|PubMed:29166604,
CC ECO:0000269|PubMed:7993622}.
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000255|PROSITE-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:0000269|PubMed:29166604, ECO:0000269|PubMed:30021165}.
CC -!- INTERACTION:
CC P50232; P49187: Mapk10; NbExp=2; IntAct=EBI-540118, EBI-7155513;
CC P50232; P49185: Mapk8; NbExp=5; IntAct=EBI-540118, EBI-7456505;
CC P50232; P21707: Syt1; NbExp=3; IntAct=EBI-540118, EBI-458098;
CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, secretory vesicle, neuronal
CC dense core vesicle membrane {ECO:0000269|PubMed:29166604,
CC ECO:0000305|PubMed:30021165}; Single-pass membrane protein
CC {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Widely expressed (PubMed:7892240). Expressed in the
CC brain (PubMed:7892240). Expressed in pituitary gland, cerebellum,
CC cortex, hypothalamus and hippocampus (PubMed:7892240).
CC {ECO:0000269|PubMed:7892240, ECO:0000269|PubMed:7993622}.
CC -!- INDUCTION: Up-regulated by potassium depolarization, calcium ionophore,
CC ATP and forskolin in culture cells (PubMed:7892240). Up-regulated by
CC kainate in the hippocampus and piriform cortex (PubMed:7892240).
CC {ECO:0000269|PubMed:7892240}.
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:0000269|PubMed:7993622, ECO:0000269|PubMed:9162066}.
CC -!- PTM: Phosphorylation at Ser-135 by MAPK8/JNK1 reduces interaction with
CC KIF1A and neuronal dense core vesicles mobility.
CC {ECO:0000269|PubMed:29166604}.
CC -!- SIMILARITY: Belongs to the synaptotagmin family. {ECO:0000305}.
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DR EMBL; U14398; AAA68519.1; -; mRNA.
DR EMBL; L38247; AAA67327.1; -; mRNA.
DR PIR; I59355; I59355.
DR RefSeq; NP_113881.1; NM_031693.2.
DR PDB; 1W15; X-ray; 1.93 A; A=288-425.
DR PDB; 1W16; X-ray; 2.30 A; A=288-425.
DR PDBsum; 1W15; -.
DR PDBsum; 1W16; -.
DR AlphaFoldDB; P50232; -.
DR SMR; P50232; -.
DR BioGRID; 249064; 1.
DR IntAct; P50232; 5.
DR MINT; P50232; -.
DR STRING; 10116.ENSRNOP00000023593; -.
DR iPTMnet; P50232; -.
DR PhosphoSitePlus; P50232; -.
DR PaxDb; P50232; -.
DR PRIDE; P50232; -.
DR Ensembl; ENSRNOT00000023594; ENSRNOP00000023593; ENSRNOG00000017333.
DR GeneID; 64440; -.
DR KEGG; rno:64440; -.
DR UCSC; RGD:68397; rat.
DR CTD; 6860; -.
DR RGD; 68397; Syt4.
DR eggNOG; KOG1028; Eukaryota.
DR GeneTree; ENSGT00940000159026; -.
DR HOGENOM; CLU_023008_7_3_1; -.
DR InParanoid; P50232; -.
DR OMA; DFPRRQI; -.
DR OrthoDB; 925064at2759; -.
DR PhylomeDB; P50232; -.
DR TreeFam; TF315600; -.
DR EvolutionaryTrace; P50232; -.
DR PRO; PR:P50232; -.
DR Proteomes; UP000002494; Chromosome 18.
DR Bgee; ENSRNOG00000017333; Expressed in cerebellum and 9 other tissues.
DR Genevisible; P50232; RN.
DR GO; GO:0097449; C:astrocyte projection; IDA:ParkinsonsUK-UCL.
DR GO; GO:0030424; C:axon; IMP:UniProtKB.
DR GO; GO:0030425; C:dendrite; ISO:RGD.
DR GO; GO:0031045; C:dense core granule; IDA:ParkinsonsUK-UCL.
DR GO; GO:0070382; C:exocytic vesicle; IDA:ParkinsonsUK-UCL.
DR GO; GO:0098978; C:glutamatergic synapse; ISO:RGD.
DR GO; GO:0005794; C:Golgi apparatus; IDA:ParkinsonsUK-UCL.
DR GO; GO:0016021; C:integral component of membrane; NAS:ParkinsonsUK-UCL.
DR GO; GO:0099066; C:integral component of neuronal dense core vesicle membrane; ISO:RGD.
DR GO; GO:0098675; C:intrinsic component of neuronal dense core vesicle membrane; IDA:UniProtKB.
DR GO; GO:1990742; C:microvesicle; ISO:RGD.
DR GO; GO:0043005; C:neuron projection; IDA:ParkinsonsUK-UCL.
DR GO; GO:0044306; C:neuron projection terminus; IDA:ParkinsonsUK-UCL.
DR GO; GO:0043025; C:neuronal cell body; IDA:ParkinsonsUK-UCL.
DR GO; GO:0098992; C:neuronal dense core vesicle; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; ISO:RGD.
DR GO; GO:0030667; C:secretory granule membrane; IDA:ParkinsonsUK-UCL.
DR GO; GO:0036477; C:somatodendritic compartment; ISO:RGD.
DR GO; GO:0045202; C:synapse; IBA:GO_Central.
DR GO; GO:0008021; C:synaptic vesicle; IDA:ParkinsonsUK-UCL.
DR GO; GO:0031982; C:vesicle; ISO:RGD.
DR GO; GO:0005509; F:calcium ion binding; ISO:RGD.
DR GO; GO:0005544; F:calcium-dependent phospholipid binding; ISO:RGD.
DR GO; GO:0030276; F:clathrin binding; IDA:BHF-UCL.
DR GO; GO:0001786; F:phosphatidylserine binding; IDA:RGD.
DR GO; GO:0046982; F:protein heterodimerization activity; IPI:ParkinsonsUK-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:ParkinsonsUK-UCL.
DR GO; GO:0000149; F:SNARE binding; IDA:RGD.
DR GO; GO:0019905; F:syntaxin binding; IPI:ParkinsonsUK-UCL.
DR GO; GO:0017075; F:syntaxin-1 binding; IPI:ParkinsonsUK-UCL.
DR GO; GO:0030348; F:syntaxin-3 binding; IPI:ParkinsonsUK-UCL.
DR GO; GO:0007420; P:brain development; IEP:RGD.
DR GO; GO:0017156; P:calcium-ion regulated exocytosis; 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; IMP:UniProtKB.
DR GO; GO:0007613; P:memory; ISO:RGD.
DR GO; GO:0045955; P:negative regulation of calcium ion-dependent exocytosis; IDA:RGD.
DR GO; GO:0033604; P:negative regulation of catecholamine secretion; IGI:ParkinsonsUK-UCL.
DR GO; GO:1905414; P:negative regulation of dense core granule exocytosis; IMP:ParkinsonsUK-UCL.
DR GO; GO:0046929; P:negative regulation of neurotransmitter secretion; IDA:ParkinsonsUK-UCL.
DR GO; GO:0050709; P:negative regulation of protein secretion; ISO:RGD.
DR GO; GO:1905433; P:negative regulation of retrograde trans-synaptic signaling by neuropeptide; ISO:RGD.
DR GO; GO:0048174; P:negative regulation of short-term neuronal synaptic plasticity; ISO:RGD.
DR GO; GO:2000301; P:negative regulation of synaptic vesicle exocytosis; ISO:RGD.
DR GO; GO:0031339; P:negative regulation of vesicle fusion; IDA:ParkinsonsUK-UCL.
DR GO; GO:0007269; P:neurotransmitter secretion; ISO:RGD.
DR GO; GO:1903861; P:positive regulation of dendrite extension; ISO:RGD.
DR GO; GO:1905415; P:positive regulation of dense core granule exocytosis; ISO:RGD.
DR GO; GO:0014049; P:positive regulation of glutamate secretion; ISO:RGD.
DR GO; GO:0017158; P:regulation of calcium ion-dependent exocytosis; ISO:RGD.
DR GO; GO:0014059; P:regulation of dopamine secretion; ISO:RGD.
DR GO; GO:0030100; P:regulation of endocytosis; IMP:ParkinsonsUK-UCL.
DR GO; GO:0099161; P:regulation of presynaptic dense core granule exocytosis; ISO:RGD.
DR GO; GO:0031338; P:regulation of vesicle fusion; IMP:ParkinsonsUK-UCL.
DR GO; GO:0061792; P:secretory granule maturation; IMP:ParkinsonsUK-UCL.
DR GO; GO:0099183; P:trans-synaptic signaling by BDNF, modulating synaptic transmission; ISO:RGD.
DR GO; GO:0006906; P:vesicle fusion; IBA:GO_Central.
DR GO; GO:0061782; P:vesicle fusion with vesicle; IMP:ParkinsonsUK-UCL.
DR GO; GO:0016192; P:vesicle-mediated transport; IBA:GO_Central.
DR Gene3D; 2.60.40.150; -; 2.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR035892; C2_domain_sf.
DR InterPro; IPR001565; Synaptotagmin.
DR InterPro; IPR028683; SYT4.
DR PANTHER; PTHR10024:SF114; PTHR10024:SF114; 1.
DR Pfam; PF00168; C2; 2.
DR PRINTS; PR00399; SYNAPTOTAGMN.
DR SMART; SM00239; C2; 2.
DR SUPFAM; SSF49562; SSF49562; 2.
DR PROSITE; PS50004; C2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium; Cytoplasmic vesicle; Differentiation; Membrane;
KW Metal-binding; Phosphoprotein; Reference proteome; Repeat; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..425
FT /note="Synaptotagmin-4"
FT /id="PRO_0000183950"
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 102..121
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 126..147
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 107..121
FT /note="Polar residues"
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:0000269|PubMed:29166604,
FT ECO:0007744|PubMed:22673903"
FT MUTAGEN 135
FT /note="S->A: Increases interaction with KIF1A. Abolishes
FT neuronal dense core vesicles mobility inhibition."
FT /evidence="ECO:0000269|PubMed:29166604"
FT MUTAGEN 135
FT /note="S->E: Decreases interaction with KIF1A. Inhibits
FT neuronal dense core vesicles mobility."
FT /evidence="ECO:0000269|PubMed:29166604"
FT MUTAGEN 244
FT /note="S->D: Restores Ca(2+)-binding and Ca(2+)-dependent
FT phospholipid binding."
FT /evidence="ECO:0000269|PubMed:9162066"
FT STRAND 290..298
FT /evidence="ECO:0007829|PDB:1W15"
FT TURN 299..302
FT /evidence="ECO:0007829|PDB:1W15"
FT STRAND 303..313
FT /evidence="ECO:0007829|PDB:1W15"
FT STRAND 325..333
FT /evidence="ECO:0007829|PDB:1W15"
FT STRAND 336..342
FT /evidence="ECO:0007829|PDB:1W15"
FT STRAND 350..361
FT /evidence="ECO:0007829|PDB:1W15"
FT STRAND 364..367
FT /evidence="ECO:0007829|PDB:1W15"
FT STRAND 370..378
FT /evidence="ECO:0007829|PDB:1W15"
FT STRAND 386..394
FT /evidence="ECO:0007829|PDB:1W15"
FT HELIX 400..410
FT /evidence="ECO:0007829|PDB:1W15"
FT STRAND 416..421
FT /evidence="ECO:0007829|PDB:1W15"
SQ SEQUENCE 425 AA; 47685 MW; 6AC88E00878936BB CRC64;
MAPITTSRVE FDEIPTVVGI FSAFGLVFTV SLFAWICCQR RSAKSNKTPP YKFVHVLKGV
DIYPENLSSK KKFGGDDKSE AKRKAALPNL SLHLDLEKRD LNGNFPKTNP KAGSSSDLEN
VTPKLFPETE KEAVSPESLK SSTSLTSEEK QEKLGTLFLS LEYNFEKKAF VVNIKEAQGL
PAMDEQSMTS DPYIKMTILP EKKHKVKTRV LRKTLDPVFD ETFTFYGVPY PHIQELSLHF
TVLSFDRFSR DDVIGEVLVP LSGIELSDGK MLMTREIIKR NAKKSSGRGE LLVSLCYQST
TNTLTVVVLK ARHLPKSDVS GLSDPYVKVN LYHAKKRISK KKTHVKKCTP NAVFNELFVF
DIPCESLEEI SVEFLVLDSE RGSRNEVIGR LVLGATAEGS GGGHWKEICD FPRRQIAKWH
MLCDG
