Synaptotagmin: Difference between revisions

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<StructureSection load='4npk' size='340' side='right' caption='Caption for this structure' scene=''>
<StructureSection load='4npk' size='340' side='right' caption='Synaptostagmin-2 C2A and C2B domains complex with Ca+2 ions (green) (PDB code [[4npk]])' scene='80/802718/Cv/1'>
__TOC__
== Function ==


== Function ==
'''Synaptotagmin''' (SYT) are calcium-binding proteins which are conserved from nematodes to humans.  Fifteen SYTs have been identified in mammals<ref>PMID:18468511</ref>. '''Synaptotagmin-1''' (SYT1) is a synaptic vesicle membrane protein and is a sensor which induces release in neurons upon binding of Ca+2 ions<ref>PMID:19412166</ref>.  The C2A domain of SYT binds phospholipids in Ca+2-dependent manner<ref>PMID:9730811</ref>.  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<ref>PMID:7559535</ref>.


'''Synaptotagmin''' (SYT) are calcium-binding proteins which are conserved from nematodes to humans.  Fifteen SYTs have been identified in mammals<ref>PMID:18468511</ref>. '''Synaptotagmin-1''' (SYT1) is a synaptic vesicle membrane protein and is a sensor which induces release in neurons upon binding of Ca+2 ions<ref>PMID:19412166</ref>. The C2A domain of SYT binds phospholipids in Ca+2-dependent manner<ref>PMID:9730811</ref>. 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<ref>PMID:7559535</ref>.  
*'''Synaptotagmin-2''' is a Ca+2 sensor for fast neurotransmitter release in caudal brain regions<ref>PMID:17192432</ref>.
*'''Synaptotagmin-3''' is a Ca+2 sensor for fast neurotransmitter release in presynapses<ref>PMID:36261524</ref>.
*'''Synaptotagmin-4''' regulates membrane traffic in neurons<ref>PMID:31743468</ref>.
*'''Synaptotagmin-5''' is dense-core vesicle-specific controlling Ca+2-regulated secretion<ref>PMID:12006594</ref>.
*'''Synaptotagmin-7''' is a plasma membrane Ca+2 sensor in synaptic exocytosis<ref>PMID:11395007</ref>.
*'''Synaptotagmin-13''' is a Ca+2-independent regulator of endocrine cell aggression and islet formation<ref>PMID:35927244</ref>.
*'''Synaptotagmin-like proteins''' (SYTL) are required in a generation of a single apical surface per cell<ref>PMID:22820376</ref>.
*'''Synaptotagmin-like protein 4''' (SYTL4) is involved in intracellular membrane trafficking.


== Relevance ==
== Relevance ==
Line 11: Line 20:
== Structural highlights ==
== 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<ref>PMID:24373768</ref>.
SYT-2 structure contains the SMP (synaptotagmin-like-mitochondrial-lipid binding) domain, followed by the <scene name='80/802718/Cv/12'>C2A Ca+2-binding, C2B</scene>, 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<ref>PMID:24373768</ref>.
 
*<scene name='80/802718/Cv/8'>1st Ca+2 binding site</scene>. Water molecules are shown as red spheres.
</StructureSection>
*<scene name='80/802718/Cv/9'>2nd Ca+2 binding site</scene>.
*<scene name='80/802718/Cv/10'>3th Ca+2 binding site</scene>.
*<scene name='80/802718/Cv/11'>All Ca+2 binding sites</scene>.


==3D structures of synaptotagmin==
==3D structures of synaptotagmin==
[[Synaptotagmin 3D structures]]


Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
</StructureSection>
{{#tree:id=OrganizedByTopic|openlevels=0|
 
*Synaptotagmin-1; domains: toxin-binding 33-53; C2A 141-268; C2B 267-446
 
**[[3f00]], [[3f01]], [[3f04]], [[3f05]] – hSYT1 C2A domain – human <br />
**[[2k45]] – hSYT1 C2A domain - NMR<br />
**[[2r83]] – hSYT1 C2A+C2B domains  <br />
**[[5t0r]], [[5vfe]] – mSYT1 C2A domain – mouse <br />
**[[1rsy]], [[4wee]] – rSYT1 C2A domain – rat <br />
**[[1k5w]], [[1byn]] – rSYT1 C2A domain - NMR<br />
**[[1tjx]], [[1tjm]], [[1uov]], [[1uow]] – rSYT1 C2B domain <br />
**[[5ccj]] – rSYT1 C2B domain (mutant)  <br />
**[[5vff]], [[5vfg]], [[5t0s]] – mSYT1 C2B domain <br />
 
*Synaptotagmin-1 complex
 
**[[2lha]] – hSYT1 C2B domain + inositol hexaphosphate - NMR<br />
**[[2yoa]] – rSYT1 C2B domain + phosphoserine<br />
**[[4v11]] – hSYT1 C2B domain + synaptic vesicle glycoprotein peptide<br />
**[[2k4a]] – hSYT1 C2A domain + heparin-binding growth factor - NMR<br />
**[[2ki6]] – hSYT1 C2A domain + heparin-binding growth factor + protein S100 A13<br />
**[[4isq]] – hSYT1 toxin-binding domain + botulinum neurotoxin DC heavy chain<br />
**[[2n1t]] – hSYT1 C2B domain + VAMP-2 + syntaxin-1A + SNAP-25 <br />
**[[5w5d]], [[5w5c]] – rSYT1 C2B domain + VAMP-2 + syntaxin-1A + SNAP-25 + complexin-1<br />
**[[5cch]], [[5ccg]], [[5kj7]], [[5cci]], [[5kj8]] – rSYT1 C2A+C2B domains + VAMP-2 + syntaxin-1A + SNAP-25 <br />
 
*Synaptotagmin-2
 
**[[2np0]], [[4kbb]] – mSYT2 ectodomain 1-60 + botulinum neurotoxin B<br />
**[[4isr]] – rSYT2 toxin-binding domain + botulinum neurotoxin DC heavy chain<br />
**[[2nm1]] – rSYT2 toxin-binding domain + botulinum neurotoxin B receptor-binding domain<br />
**[[4npk]], [[4npj]] – hSYT2 C2A+C2B domains  363-662<br />
**[[4npi]] – hSYT2 SMP+C2A+C2B domains  191-662<br />
 
*Synaptotagmin-3
 
**[[3hn8]] – rSYT3 C2A+C2B domains 293-588 <br />
**[[1dqv]] – rSYT3 C2A+C2B domains - NMR<br />
 
*Synaptotagmin-4
 
**[[1ugk]] – hSYT4 C2A domain - NMR<br />
**[[1w15]], [[1w16]] – rSYT4 C2B domain<br />
 
*Synaptotagmin-5
 
**[[5h4y]] – hSYT5 C2A domain<br />
**[[5h4z]] – hSYT5 C2A domain (mutant)<br />
 
*Synaptotagmin-7
 
**[[2d8k]] – hSYT7 C2A domain - NMR<br />
**[[6anj]] – rSYT7 C2A domain  <br />
**[[3n5a]] – mSYT7 C2B domain 266-403 <br />
**[[6ank]] – rSYT7 C2A+C2B domains  <br />
 
*Synaptotagmin-13
 
**[[1wfm]] – hSYT13 C2A domain - NMR<br />
}}
 
 
 


== References ==
== References ==
<references/>
<references/>
[[Category:Topic Page]]
[[Category:Topic Page]]

Latest revision as of 11:46, 15 August 2024

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 , 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].

  • . Water molecules are shown as red spheres.
  • .
  • .
  • .

3D structures of synaptotagmin

Synaptotagmin 3D structures


Synaptostagmin-2 C2A and C2B domains complex with Ca+2 ions (green) (PDB code 4npk)

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ 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:http://dx.doi.org/10.1016/j.bbrc.2008.04.174
  2. ↑ 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:http://dx.doi.org/10.1038/nn.2320
  3. ↑ 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:http://dx.doi.org/10.1021/bi9807512
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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:http://dx.doi.org/10.1038/ncb2541
  12. ↑ 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:http://dx.doi.org/10.1186/s13195-016-0208-8
  13. ↑ 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:http://dx.doi.org/10.1016/j.str.2013.11.011

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