SYT1 explained

Synaptotagmin-1 is a protein that in humans is encoded by the SYT1 gene.^[1]

Function

Synaptotagmins are integral membrane proteins of synaptic vesicles thought to serve as sensors for calcium ions (Ca²⁺) in the process of vesicular trafficking and exocytosis. Calcium ion binding to synaptotagmin I participates in triggering neurotransmitter release at the synapse.^[2] [Supplied by [[Online Mendelian Inheritance in Man|OMIM]]]^[3]

SYT1 is the master switch responsible for allowing the human brain to release neurotransmitters. SYT1 senses calcium ion concentrations as low as 10 ppm and subsequently signals the SNARE complex to open fusion pores.^[4]

Interactions

SYT1 has been shown to interact with SNAP-25,^{[5] [6]} STX1A^{[7] [8]} and S100A13.^{[9] [10]}

Clinical Significance

Mutations in the SYT1 gene cause a rare neurodevelopmental disorder known as SYT1-associated neurodevelopmental disorder (or Baker-Gordon Syndrome).^{[11] [12]}

Further reading

• Mochly-Rosen D, Miller KG, Scheller RH, Khaner H, Lopez J, Smith BL . p65 fragments, homologous to the C2 region of protein kinase C, bind to the intracellular receptors for protein kinase C . Biochemistry . 31 . 35 . 8120–4 . Sep 1992 . 1326322 . 10.1021/bi00150a003 .
• McMahon HT, Missler M, Li C, Südhof TC . Complexins: cytosolic proteins that regulate SNAP receptor function . Cell . 83 . 1 . 111–9 . Oct 1995 . 7553862 . 10.1016/0092-8674(95)90239-2 . 675343 . free .
• O'Regan S, Diebler MF, Meunier FM, Vyas S . A Ewing's sarcoma cell line showing some, but not all, of the traits of a cholinergic neuron . Journal of Neurochemistry . 64 . 1 . 69–76 . Jan 1995 . 7798952 . 10.1046/j.1471-4159.1995.64010069.x . 20958851 .
• Zhang JZ, Davletov BA, Südhof TC, Anderson RG . Synaptotagmin I is a high affinity receptor for clathrin AP-2: implications for membrane recycling . Cell . 78 . 5 . 751–60 . Sep 1994 . 8087843 . 10.1016/S0092-8674(94)90442-1 . 44550431 .
• Chapman ER, Blasi J, An S, Brose N, Johnston PA, Südhof TC, Jahn R . Fatty acylation of synaptotagmin in PC12 cells and synaptosomes . Biochemical and Biophysical Research Communications . 225 . 1 . 326–32 . Aug 1996 . 8769138 . 10.1006/bbrc.1996.1174 . free .
• Perin MS . Mirror image motifs mediate the interaction of the COOH terminus of multiple synaptotagmins with the neurexins and calmodulin . Biochemistry . 35 . 43 . 13808–16 . Oct 1996 . 8901523 . 10.1021/bi960853x .
• Betz A, Okamoto M, Benseler F, Brose N . Direct interaction of the rat unc-13 homologue Munc13-1 with the N terminus of syntaxin . The Journal of Biological Chemistry . 272 . 4 . 2520–6 . Jan 1997 . 8999968 . 10.1074/jbc.272.4.2520 . free .
• Shao X, Li C, Fernandez I, Zhang X, Südhof TC, Rizo J . Synaptotagmin-syntaxin interaction: the C2 domain as a Ca2+-dependent electrostatic switch . Neuron . 18 . 1 . 133–42 . Jan 1997 . 9010211 . 10.1016/S0896-6273(01)80052-0 . 17947552 . free .
• Charvin N, L'evêque C, Walker D, Berton F, Raymond C, Kataoka M, Shoji-Kasai Y, Takahashi M, De Waard M, Seagar MJ . Direct interaction of the calcium sensor protein synaptotagmin I with a cytoplasmic domain of the alpha1A subunit of the P/Q-type calcium channel . The EMBO Journal . 16 . 15 . 4591–6 . Aug 1997 . 9303303 . 1170085 . 10.1093/emboj/16.15.4591 .
• Mouta Carreira C, LaVallee TM, Tarantini F, Jackson A, Lathrop JT, Hampton B, Burgess WH, Maciag T . S100A13 is involved in the regulation of fibroblast growth factor-1 and p40 synaptotagmin-1 release in vitro . The Journal of Biological Chemistry . 273 . 35 . 22224–31 . Aug 1998 . 9712836 . 10.1074/jbc.273.35.22224 . free . 2158/26736 . free .
• Thomas DM, Ferguson GD, Herschman HR, Elferink LA . Functional and biochemical analysis of the C2 domains of synaptotagmin IV . Molecular Biology of the Cell . 10 . 7 . 2285–95 . Jul 1999 . 10397765 . 25443 . 10.1091/mbc.10.7.2285 .
• Gerona RR, Larsen EC, Kowalchyk JA, Martin TF . The C terminus of SNAP25 is essential for Ca(2+)-dependent binding of synaptotagmin to SNARE complexes . The Journal of Biological Chemistry . 275 . 9 . 6328–36 . Mar 2000 . 10692432 . 10.1074/jbc.275.9.6328 . free .
• Mizutani A, Fukuda M, Ibata K, Shiraishi Y, Mikoshiba K . SYNCRIP, a cytoplasmic counterpart of heterogeneous nuclear ribonucleoprotein R, interacts with ubiquitous synaptotagmin isoforms . The Journal of Biological Chemistry . 275 . 13 . 9823–31 . Mar 2000 . 10734137 . 10.1074/jbc.275.13.9823 . free .
• Kimura N, Shiraishi S, Mizunashi K, Ohtsu H, Kimura I . Synaptotagmin I expression in mast cells of normal human tissues, systemic mast cell disease, and a human mast cell leukemia cell line . The Journal of Histochemistry and Cytochemistry . 49 . 3 . 341–6 . Mar 2001 . 11181737 . 10.1177/002215540104900308 . free .
• Fernández-Chacón R, Königstorfer A, Gerber SH, García J, Matos MF, Stevens CF, Brose N, Rizo J, Rosenmund C, Südhof TC . Synaptotagmin I functions as a calcium regulator of release probability . Nature . 410 . 6824 . 41–9 . Mar 2001 . 11242035 . 10.1038/35065004 . 1756258 .
• Fukuda M, Mikoshiba K . Synaptotagmin-like protein 1-3: a novel family of C-terminal-type tandem C2 proteins . Biochemical and Biophysical Research Communications . 281 . 5 . 1226–33 . Mar 2001 . 11243866 . 10.1006/bbrc.2001.4512 .
• Martina JA, Bonangelino CJ, Aguilar RC, Bonifacino JS . Stonin 2: an adaptor-like protein that interacts with components of the endocytic machinery . The Journal of Cell Biology . 153 . 5 . 1111–20 . May 2001 . 11381094 . 2174325 . 10.1083/jcb.153.5.1111 .
• Landriscina M, Bagalá C, Mandinova A, Soldi R, Micucci I, Bellum S, Prudovsky I, Maciag T . Copper induces the assembly of a multiprotein aggregate implicated in the release of fibroblast growth factor 1 in response to stress . The Journal of Biological Chemistry . 276 . 27 . 25549–57 . Jul 2001 . 11432880 . 10.1074/jbc.M102925200 . free .
• Coppola T, Magnin-Luthi S, Perret-Menoud V, Gattesco S, Schiavo G, Regazzi R . Direct interaction of the Rab3 effector RIM with Ca2+ channels, SNAP-25, and synaptotagmin . The Journal of Biological Chemistry . 276 . 35 . 32756–62 . Aug 2001 . 11438518 . 10.1074/jbc.M100929200 . free .

Notes and References

1. Perin MS, Johnston PA, Ozcelik T, Jahn R, Francke U, Südhof TC . Structural and functional conservation of synaptotagmin (p65) in Drosophila and humans . The Journal of Biological Chemistry . 266 . 1 . 615–22 . Jan 1991 . 10.1016/S0021-9258(18)52479-0 . 1840599 . free .
2. Fernández-Chacón R, Königstorfer A, Gerber SH, García J, Matos MF, Stevens CF, Brose N, Rizo J, Rosenmund C, Südhof TC . Synaptotagmin I functions as a calcium regulator of release probability . Nature . 410 . 6824 . 41–9 . March 2001 . 11242035 . 10.1038/35065004 . 1756258 .
3. Web site: Entrez Gene: SYT1 synaptotagmin I.
4. Lee HK, Yang Y, Su Z, Hyeon C, Lee TS, Lee HW, Kweon DH, Shin YK, Yoon TY . Dynamic Ca2+-dependent stimulation of vesicle fusion by membrane-anchored synaptotagmin 1 . Science . 328 . 5979 . 760–3 . May 2010 . 20448186 . 2994549 . 10.1126/science.1187722 .
   • Brain's master switch is verified . May 9, 2010 . ScienceDaily.
5. Gerona RR, Larsen EC, Kowalchyk JA, Martin TF . The C terminus of SNAP25 is essential for Ca(2+)-dependent binding of synaptotagmin to SNARE complexes . The Journal of Biological Chemistry . 275 . 9 . 6328–36 . Mar 2000 . 10692432 . 10.1074/jbc.275.9.6328 . free .
6. Zhang X, Kim-Miller MJ, Fukuda M, Kowalchyk JA, Martin TF . Ca2+-dependent synaptotagmin binding to SNAP-25 is essential for Ca2+-triggered exocytosis . Neuron . 34 . 4 . 599–611 . May 2002 . 12062043 . 10.1016/S0896-6273(02)00671-2 . 16768299 . free .
7. Shao X, Li C, Fernandez I, Zhang X, Südhof TC, Rizo J . Synaptotagmin-syntaxin interaction: the C2 domain as a Ca2+-dependent electrostatic switch . Neuron . 18 . 1 . 133–42 . Jan 1997 . 9010211 . 10.1016/S0896-6273(01)80052-0 . 17947552 . free .
8. Thomas DM, Ferguson GD, Herschman HR, Elferink LA . Functional and biochemical analysis of the C2 domains of synaptotagmin IV . Molecular Biology of the Cell . 10 . 7 . 2285–95 . Jul 1999 . 10397765 . 25443 . 10.1091/mbc.10.7.2285 .
9. Mouta Carreira C, LaVallee TM, Tarantini F, Jackson A, Lathrop JT, Hampton B, Burgess WH, Maciag T . S100A13 is involved in the regulation of fibroblast growth factor-1 and p40 synaptotagmin-1 release in vitro . The Journal of Biological Chemistry . 273 . 35 . 22224–31 . Aug 1998 . 9712836 . 10.1074/jbc.273.35.22224 . free . 2158/26736 . free .
10. Landriscina M, Bagalá C, Mandinova A, Soldi R, Micucci I, Bellum S, Prudovsky I, Maciag T . Copper induces the assembly of a multiprotein aggregate implicated in the release of fibroblast growth factor 1 in response to stress . The Journal of Biological Chemistry . 276 . 27 . 25549–57 . Jul 2001 . 11432880 . 10.1074/jbc.M102925200 . free .
11. Baker K, Gordon SL, Melland H, et al. . 2018 . SYT1-associated neurodevelopmental disorder: a case series . Brain . 141. 9 . 2576–2591. 10.1093/brain/awy209 . free . 6113648. 30107533 .
12. Web site: OMIM entry: Baker-Gordon Syndrome .