Synaptotagmin

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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.

Functions

Synaptotagmin is a 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]

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.^[6]

C-terminal C2-domains

The C2A domain regulates the fusion step of synaptic vesicle exocytosis.^[7][8] Consistent with this, the kinetics of Ca^{2 +} -dependent phospholipid binding activity of the C2A domain in vitro are compatible with the very fast nature of neurotransmitter release (within 200 μs).^[9] The C2A domain was shown to bind negatively charged phospholipids in a Ca^{2 +} -dependent fashion. Ca^{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 Ca^{2 +} -dependent self-clustering via the C2B domain. Ca^{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.

References and notes