Synaptotagmin

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File:Exocytosis-machinery.jpg
Molecular machinery driving exocytosis in neurotransmitter release: the core SNARE complex (formed by four -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.

Functions

Synaptotagmin is Ca2+ sensor and is involved in both:

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 -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 -dependent fashion. -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 -dependent self-clustering via the C2B domain. -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

  1. 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.
  2. 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.
  3. 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.
  4. Maximov A, Südhof TC (2005). "Autonomous function of synaptotagmin 1 in triggering synchronous release independent of asynchronous release". Neuron. 48: 547–554.
  5. O'Connor V, Lee AG (2002). "Synaptic vesicle fusion and synaptotagmin: 2B or not 2B?". Nature Neuroscience. 5: 823–824.
  6. 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.
  7. Zimmerberg J, Akimov SA, Frolov V (2006). "Synaptotagmin: fusogenic role for calcium sensor?". Nature Structural & Molecular Biology. 13: 301–303.
  8. 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.
  9. Chapman ER (2002). "Synaptotagmin: A Ca2+ sensor that triggers exocytosis?" (PDF). Nature Reviews Molecular Cell Biology. 3: 498–508.

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