Synaptotagmin

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Molecular machinery driving exocytosis in neurotransmitter release: the core SNARE complex (formed by four

α

-helices contributed by synaptobrevin, syntaxin and SNAP-25) and the Ca²⁺ sensor synaptotagmin.

Synaptotagmins (isotypes Syt1-Syt13) constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region (TMR), a variable linker, and two C-terminal C2-domains - C2A and C2B.

1 Functions
2 C-terminal C2-domains
3 Displacement of complexin
4 References and notes
5 External links

Synaptotagmin is Ca²⁺ sensor and is involved in both:

(i) early synaptic vesicle docking to the presynaptic membrane via interaction with β-neurexin^[1] or SNAP-25^[2]
(ii) late steps of Ca²⁺ evoked synaptic vesicle fusion with the presynaptic membrane.^[3]^[4]^[5]

The C2A domain regulates the fusion step of synaptic vesicle exocytosis.^[6]^[7] Consistent with this, the kinetics of $C a 2 +$ -dependent phospholipid binding activity of the C2A domain in vitro are compatible with the very fast nature of neurotransmitter release (within 200 μs).^[8] The C2A domain was shown to bind negatively charged phospholipids in a $C a 2 +$ -dependent fashion. $C a 2 +$ -binding alters the protein-protein interactions of synaptotagmin such as increasing the affinity of synaptotagmin for syntaxin.

The C2B domain binds to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence, suggesting that a lipid-interaction switch occurs during depolarization. Ca²⁺-binding to the C2B domain confers synaptotagmin dimerization involved in the fusion step of synaptic vesicles by $C a 2 +$ -dependent self-clustering via the C2B domain. $C a 2 +$ -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.

It was recently shown that synaptotagmin 1 can displace complexin from the SNARE complex in the presence of calcium. This is thought to be one of the last steps in exocytosis.^[9]

^ Fukuda M, Moreira JE, Liu V, Sugimori M, Mikoshiba K, Llinas RR (2000). "Role of the conserved WHXL motif in the C terminus of synaptotagmin in synaptic vesicle docking". Proc Natl Acad Sci USA 97: 14715-14719.
^ Schiavo G, Stenbeck G, Rothman JE, Söllner TH (1997). "Binding of the synaptic vesicle v-SNARE, synaptotagmin, to the plasma membrane t-SNARE, SNAP-25, can explain docked vesicles at neurotoxin-treated synapses". Proc Natl Acad Sci USA 94: 997-1001.
^ Pang ZP, Melicoff E, Padgett D, Liu Y, Teich AF, Dickey BF, et al. (2006). "Synaptotagmin-2 is essential for survival and contributes to Ca²⁺ triggering of neurotransmitter release in central and neuromuscular synapses". The Journal of Neuroscience 26: 13493-13504.
^ Maximov A, Südhof TC (2005). "Autonomous function of synaptotagmin 1 in triggering synchronous release independent of asynchronous release". Neuron 48: 547-554.
^ O'Connor V, Lee AG (2002). "Synaptic vesicle fusion and synaptotagmin: 2B or not 2B?". Nature Neuroscience 5: 823-824.
^ Zimmerberg J, Akimov SA, Frolov V (2006). "Synaptotagmin: fusogenic role for calcium sensor?". Nature Structural & Molecular Biology 13: 301-303.
^ Fernández-Chacón R, Königstorfer A, Gerber SH, García J, Matos MF, Stevens CF, et al. (2001). "Synaptotagmin I functions as a calcium regulator of release probability". Nature 410: 41-49.
^ Chapman ER (2002). "Synaptotagmin: A Ca²⁺ sensor that triggers exocytosis?". Nature Reviews Molecular Cell Biology 3: 498-508.
^ Tang J, Maximov A, Shin OH, Dai H, Rizo J, Südhof TC (2006). "A complexin/synaptotagmin 1 switch controls fast synaptic vesicle exocytosis". Cell 126 (6): 1175-1187.