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[[File:Exocytosis-machinery.jpg|thumb|360px|Molecular machinery driving exocytosis in neurotransmitter release: the [[SNARE (protein)|core SNARE complex]] (formed by four <math>\alpha</math>-helices contributed by [[synaptobrevin]], [[syntaxin]] and [[SNAP-25]]) and the Ca<sup>2+</sup> [[sensor]] synaptotagmin.<ref name="Georgiev2007">{{cite book
  | last = Georgiev
  | first = Danko D .
  | coauthors = James F . Glazebrook
  | chapter = Subneuronal processing of information by solitary waves and stochastic processes
  | title = Nano and Molecular Electronics Handbook
  | publisher = CRC Press
  | series = Nano and Microengineering Series
  | editor-last = Lyshevski
  | editor-first = Sergey Edward
  | volume = 
  | pages = 17-1–17-41
  | year = 2007
  | url = http://www.crcnetbase.com/doi/abs/10.1201/9781420008142.ch17
  | isbn = 978-0-8493-8528-5
}}</ref>]]  

'''Synaptotagmins'''  constitute a family of [[cell membrane|membrane]]-trafficking [[proteins]] that are characterized by an N-terminal transmembrane region (TMR), a variable linker, and two C-terminal [[C2 domain]]s - C2A and C2B. There are 15 members in the mammalian synaptotagmin family. There are several C2-domain containing protein families that are related to synaptotagmins, including transmembrane (Ferlins, E-Syts, and MCTPs) and soluble (RIMs, Munc13s, synaptotagmin-related proteins and B/K) proteins. 

==Functions==
Based on their brain/endocrine distribution and biochemical properties, in particular C2 domains of certain synaptotagmins bound to calcium, synaptotagmins were proposed to function as calcium sensors in the regulation of neurotransmitter release and hormone secretion. Although synaptotagmins share a similar domain structure and a high degree of homology in the C2 domains, not all synaptotagmins bind to calcium. In fact, only eight out of the fifteen synaptotagmins are capable of calcium binding. The calcium binding synaptotagmins include synaptotagmins 1, 2, 3, 5, 6, 7, 9, and 10. The remaining seven synaptotagmins do not bind to calcium due to the lack of calcium coordinating residues or spatial orientation of the acidic residues (see the section on C2 domains for details).

Calcium-binding Synaptotagmins act as Ca<sup>2+</sup> sensors and are involved in both:
* (i) early [[exocytosis|synaptic vesicle docking]] to the presynaptic membrane via interaction with [[neurexin|β-neurexin]]<ref name="Fukuda2000">
{{cite journal
 | author = Fukuda M, Moreira JE, Liu V, Sugimori M, Mikoshiba K, Llinas RR
 | title  = Role of the conserved WHXL motif in the C terminus of synaptotagmin in synaptic vesicle docking
 | journal = Proc Natl Acad Sci USA
 | volume = 97
 | pages = 14715–14719
 | year = 2000
 | doi  = 10.1073/pnas.260491197
 | pmid = 11114192
 | issue = 26
 | pmc = 18984
}}
</ref> or [[SNAP-25]]<ref name="Schiavo1997">
{{cite journal
 | author = Schiavo G, Stenbeck G, Rothman JE, Söllner TH
 | title  = Binding of the synaptic vesicle v-SNARE, synaptotagmin, to the plasma membrane t-SNARE, SNAP-25, can explain docked vesicles at neurotoxin-treated synapses
 | journal = Proc Natl Acad Sci USA
 | volume = 94
 | pages = 997–1001
 | year = 1997
 | doi  = 10.1073/pnas.94.3.997
 | pmid = 9023371
 | issue = 3
 | pmc = 19628
}}
</ref> 
* (ii) late steps of Ca<sup>2+</sup> evoked [[synaptic vesicle]] [[exocytosis|fusion]] with the [[synapse|presynaptic membrane]].<ref name="Pang2006">
{{cite journal
 | author = Pang ZP, Melicoff E, Padgett D, Liu Y, Teich AF, Dickey BF, et al.
 | title  = Synaptotagmin-2 is essential for survival and contributes to Ca<sup>2+</sup> triggering of neurotransmitter release in central and neuromuscular synapses
 | journal = The Journal of Neuroscience
 | volume = 26
 | pages = 13493–13504
 | year = 2006
 | doi  = 10.1523/JNEUROSCI.3519-06.2006
 | pmid = 17192432
 | issue = 52
}}
</ref><ref name="Maximov2005">
{{cite journal
 | author = Maximov A, Südhof TC
 | title  = Autonomous function of synaptotagmin 1 in triggering synchronous release independent of asynchronous release
 | journal = Neuron
 | volume = 48
 | pages = 547–554
 | year = 2005
 | doi  = 10.1016/j.neuron.2005.09.006
 | pmid = 16301172
 | issue = 4
}}
</ref><ref name="O'Connor2002">
{{cite journal
 | author = O'Connor V, Lee AG
 | title  = Synaptic vesicle fusion and synaptotagmin: 2B or not 2B?
 | journal = Nature Neuroscience
 | volume = 5
 | pages = 823–824
 | year = 2002
 | doi  = 10.1038/nn0902-823
 | pmid = 12196805
 | issue = 9
}}
</ref>
It was recently shown that synaptotagmin 1 can displace [[complexin]] from the [[SNARE (protein)|SNARE complex]] in the presence of calcium.  This is thought to be one of the last steps in [[exocytosis]].<ref name="Tang2006"> 
{{cite journal
 | author = Tang J, Maximov A, Shin OH, Dai H, Rizo J, Südhof TC
 | title  = A complexin/synaptotagmin 1 switch controls fast synaptic vesicle exocytosis
 | journal = Cell
 | volume = 126
 | issue = 6
 | pages = 1175–1187
 | year = 2006
 | doi  = 10.1016/j.cell.2006.08.030
 | pmid = 16990140
}}
</ref>
Calcium bound-synaptotagmin binding to the SNARE complex, causes the fusion clamp effect of [[complexin]] to be released, allowing vesicle fusion to occur and exocytosis to proceed.<ref>{{cite pmid|19164751}} </ref>

==C-terminal C2-domains==
The C2 domain is a widely occurring conserved sequence motif of 130-140 amino acid residues, which was first defined as the second constant sequence in [[Protein Kinase C|PKC]] isoforms. The C2 domain was first shown to bind to calcium in synaptotagmin-1. Subsequent atomic structure analysis of synaptotagmin-1 at 1.9 Å resolution indicated that its C2 domains are composed of a stable eight-stranded β-sandwich with flexible loops emerging from the top and bottom. Nuclear magnetic resonance (NMR) studies of synaptotagmin-1 revealed that calcium binds exclusively to the top loops, and the binding pockets are coordinated by five conserved aspartate residues: three calcium ions bind to C2A via D172, D178, D230, D232, S235 and D238, and two calcium ions bind to C2B via D303, D309, D363, 365 and D371. Not all synaptotagmin C2 domains bind to calcium. In fact, based on sequence similarities and subsequent confirmation by biochemical analyses, only eight synaptotagmins bind to calcium, namely, synaptotagmin-1, -2, -3, -5, -6, -7, -9 and -10. The lack of critical residues involved in calcium binding accounts for the majority of failure in calcium-binding by the other synaptotagmins. This includes both C2 domains of synaptotagmin-11, -12, -13, -14 and -15, and C2A domain of synaptotagmin-4 and -8. Synaptotagmin-4 and -11 C2B domains, which possess all five acidic residues in the top loops, however, do not bind to calcium due to spatial orientation of the calcium ligands that fail to form proper calcium binding sites. For calcium-binding synaptotagmins, although amino acid residues in the top loops other than those mentioned above are not directly involved in coordinating calcium binding, they affect calcium binding affinity, such as R233 in synaptotagmin-1. The diversity of sequences and structures flanking the calcium-coordinating amino acid residues renders the eight synaptotagmins bind to calcium at various affinities, covering the full range of calcium requirements for regulated exocytosis. 

'''The C2A domain''' regulates the fusion step of [[synaptic vesicle]] [[exocytosis]].<ref name="Zimmerberg2006">
{{cite journal
 | author = Zimmerberg J, Akimov SA, Frolov V
 | title  = Synaptotagmin: fusogenic role for calcium sensor?
 | journal = Nature Structural & Molecular Biology
 | volume = 13
 | pages = 301–303
 | year = 2006
 | doi  = 10.1038/nsmb0406-301
 | pmid = 16715046
 | issue = 4
}}
</ref><ref name="Fernandez2001">
{{cite journal
 | author = Fernández-Chacón R, Königstorfer A, Gerber SH, García J, Matos MF, Stevens CF, et al.
 | title  = Synaptotagmin I functions as a calcium regulator of release probability
 | journal = Nature
 | volume = 410
 | pages = 41–49
 | year = 2001
 | doi  = 10.1038/35065004
 | pmid = 11242035
 | issue = 6824
}}
</ref> Consistent with this, the kinetics of <math>Ca^{2+}</math>-dependent phospholipid binding activity of the C2A domain ''in vitro'' are compatible with the very fast nature of neurotransmitter release (within 200 μs).<ref name="Chapman2002">
{{cite journal
 | author = Chapman ER
 | url = 
 | title  = Synaptotagmin: A Ca<sup>2+</sup> sensor that triggers exocytosis?
 | journal = Nature Reviews Molecular Cell Biology
 | volume = 3
 | pages = 498–508
 | year = 2002
 | doi  = 10.1038/nrm855
 | pmid = 12094216
 | issue = 7
 | format = 
}}
</ref> The C2A domain was shown to bind negatively charged [[phospholipids]] in a <math>Ca^{2+}</math>-dependent fashion. <math>Ca^{2+}</math>-binding alters the protein-protein interactions of synaptotagmin such as increasing the affinity of synaptotagmin for [[syntaxin]].

'''The C2B domain''' binds to [[PIP3|phosphatidyl-inositol-3,4,5-triphosphate (PIP3)]] in the absence of calcium ions and to [[PIP2|phosphatidylinositol bisphosphate (PIP2)]] in their presence, suggesting that a lipid-interaction switch occurs during [[depolarization]]. Ca<sup>2+</sup>-binding to the C2B domain confers synaptotagmin dimerization involved in the fusion step of [[synaptic vesicles]] by <math>Ca^{2+}</math>-dependent self-clustering via the C2B domain.{{Citation needed|date=June 2012}} <math>Ca^{2+}</math>-independent is the interaction between the C2B domain and [[SNAP-25]], and between the C2B domain and the "synprint" (synaptic protein interaction) motif of the pore-forming subunit of [[voltage-gated calcium channels]]. The C2B domain regulates also the recycling step of synaptic vesicles by binding to the [[clathrin]] assembly protein, AP-2.

==References and notes==
{{reflist|2}}

==External links==
* {{UMichOPM|families|superfamily|47}} - Orientations of C2 domains in the lipid bilayer
* {{MeshName|Synaptotagmins}}

{{Calcium signaling}}
{{Calcium-binding proteins}}
{{Vesicular transport proteins}}
[[Category:Peripheral membrane proteins]]