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Function
Synaptotagmin (SYT) are calcium-binding proteins which are conserved from nematodes to humans. Fifteen SYTs have been identified in mammals[1]. Synaptotagmin-1 (SYT1) is a synaptic vesicle membrane protein and is a sensor which induces release in neurons upon binding of Ca+2 ions[2]. The C2A domain of SYT binds phospholipids in Ca+2-dependent manner[3]. The C2B domain of SYT promotes binding to other C2B domains and to accessory proteins. Ca+2 binding causes intramolecular association of domains C2A and C2B. The synaptic fusion apparatus includes the affinity between SYT and Syntaxin-1, This affinity increases by ca. 2 orders of magnitude upon binding of Ca+2[4].
- Synaptotagmin-2 is a Ca+2 sensor for fast neurotransmitter release in caudal brain regions[5].
- Synaptotagmin-3 is a Ca+2 sensor for fast neurotransmitter release in presynapses[6].
- Synaptotagmin-4 regulates membrane traffic in neurons[7].
- Synaptotagmin-5 is dense-core vesicle-specific controlling Ca+2-regulated secretion[8].
- Synaptotagmin-7 is a plasma membrane Ca+2 sensor in synaptic exocytosis[9].
- Synaptotagmin-13 is a Ca+2-independent regulator of endocrine cell aggression and islet formation[10].
- Synaptotagmin-like proteins (SYTL) are required in a generation of a single apical surface per cell[11].
- Synaptotagmin-like protein 4 (SYTL4) is involved in intracellular membrane trafficking.
Relevance
Synaptotagmin-4 is up-regulated by chronic depolarization and seizures. Synaptotagmin-1 is a promising biomarker to monitor dysfunction and degeneration in Alzheimer disease[12].
Structural highlights
SYT-2 structure contains the SMP (synaptotagmin-like-mitochondrial-lipid binding) domain, followed by the C2A Ca+2-binding, C2B, spacer and C2C domains. At the cup-shaped cavity at the of SYT C2A domain there are three tightly clustered Ca+2 binding sites formed by canonical 5 aspartates[13].
3D structures of synaptotagmin
Synaptotagmin 3D structures
- ↑ Hu ZT, Chen MR, Ping Z, Dong YM, Zhang RY, Xu T, Wu ZX. Synaptotagmin IV regulates dense core vesicle (DCV) release in LbetaT2 cells. Biochem Biophys Res Commun. 2008 Jul 11;371(4):781-6. doi:, 10.1016/j.bbrc.2008.04.174. Epub 2008 May 9. PMID:18468511 doi:https://dx.doi.org/10.1016/j.bbrc.2008.04.174
- ↑ Xu J, Pang ZP, Shin OH, Sudhof TC. Synaptotagmin-1 functions as a Ca2+ sensor for spontaneous release. Nat Neurosci. 2009 Jun;12(6):759-66. doi: 10.1038/nn.2320. PMID:19412166 doi:https://dx.doi.org/10.1038/nn.2320
- ↑ Zhang X, Rizo J, Sudhof TC. Mechanism of phospholipid binding by the C2A-domain of synaptotagmin I. Biochemistry. 1998 Sep 8;37(36):12395-403. doi: 10.1021/bi9807512. PMID:9730811 doi:https://dx.doi.org/10.1021/bi9807512
- ↑ Chapman ER, Hanson PI, An S, Jahn R. Ca2+ regulates the interaction between synaptotagmin and syntaxin 1. J Biol Chem. 1995 Oct 6;270(40):23667-71. PMID:7559535
- ↑ Pang ZP, Melicoff E, Padgett D, Liu Y, Teich AF, Dickey BF, Lin W, Adachi R, Südhof TC. Synaptotagmin-2 is essential for survival and contributes to Ca2+ triggering of neurotransmitter release in central and neuromuscular synapses. J Neurosci. 2006 Dec 27;26(52):13493-504. PMID:17192432 doi:10.1523/JNEUROSCI.3519-06.2006
- ↑ Weingarten DJ, Shrestha A, Juda-Nelson K, Kissiwaa SA, Spruston E, Jackman SL. Fast resupply of synaptic vesicles requires synaptotagmin-3. Nature. 2022 Nov;611(7935):320-325. PMID:36261524 doi:10.1038/s41586-022-05337-1
- ↑ Jia Q, Hu S, Jiao D, Li X, Qi S, Fan R. Synaptotagmin-4 promotes dendrite extension and melanogenesis in alpaca melanocytes by regulating Ca(2+) influx via TRPM1 channels. Cell Biochem Funct. 2020 Apr;38(3):275-282. PMID:31743468 doi:10.1002/cbf.3465
- ↑ Saegusa C, Fukuda M, Mikoshiba K. Synaptotagmin V is targeted to dense-core vesicles that undergo calcium-dependent exocytosis in PC12 cells. J Biol Chem. 2002 Jul 5;277(27):24499-505. PMID:12006594 doi:10.1074/jbc.M202767200
- ↑ Sugita S, Han W, Butz S, Liu X, Fernandez-Chacon R, Lao Y, Sudhof TC. Synaptotagmin VII as a plasma membrane Ca(2+) sensor in exocytosis. Neuron. 2001 May;30(2):459-73. PMID:11395007
- ↑ Bakhti M, Bastidas-Ponce A, Tritschler S, Czarnecki O, Tarquis-Medina M, Nedvedova E, Jaki J, Willmann SJ, Scheibner K, Cota P, Salinno C, Boldt K, Horn N, Ueffing M, Burtscher I, Theis FJ, Coskun Ü, Lickert H. Synaptotagmin-13 orchestrates pancreatic endocrine cell egression and islet morphogenesis. Nat Commun. 2022 Aug 4;13(1):4540. PMID:35927244 doi:10.1038/s41467-022-31862-8
- ↑ Galvez-Santisteban M, Rodriguez-Fraticelli AE, Bryant DM, Vergarajauregui S, Yasuda T, Banon-Rodriguez I, Bernascone I, Datta A, Spivak N, Young K, Slim CL, Brakeman PR, Fukuda M, Mostov KE, Martin-Belmonte F. Synaptotagmin-like proteins control the formation of a single apical membrane domain in epithelial cells. Nat Cell Biol. 2012 Aug;14(8):838-49. doi: 10.1038/ncb2541. Epub 2012 Jul 22. PMID:22820376 doi:https://dx.doi.org/10.1038/ncb2541
- ↑ Ohrfelt A, Brinkmalm A, Dumurgier J, Brinkmalm G, Hansson O, Zetterberg H, Bouaziz-Amar E, Hugon J, Paquet C, Blennow K. The pre-synaptic vesicle protein synaptotagmin is a novel biomarker for Alzheimer's disease. Alzheimers Res Ther. 2016 Oct 3;8(1):41. doi: 10.1186/s13195-016-0208-8. PMID:27716408 doi:https://dx.doi.org/10.1186/s13195-016-0208-8
- ↑ Xu J, Bacaj T, Zhou A, Tomchick DR, Sudhof TC, Rizo J. Structure and Ca-Binding Properties of the Tandem C Domains of E-Syt2. Structure. 2013 Dec 24. pii: S0969-2126(13)00461-9. doi:, 10.1016/j.str.2013.11.011. PMID:24373768 doi:https://dx.doi.org/10.1016/j.str.2013.11.011
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