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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.
[edit] Functions
Synaptotagmin is a 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]
[edit] C-terminal C2-domains
The C2A domain regulates the fusion step of synaptic vesicle exocytosis.[7][8] Consistent with this, the kinetics of Ca2 + -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 Ca2 + -dependent fashion. Ca2 + -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 Ca2 + -dependent self-clustering via the C2B domain. Ca2 + -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.
[edit] References and notes
- ^ 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. doi:10.1073/pnas.260491197.
- ^ 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. doi:10.1073/pnas.94.3.997.
- ^ 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. doi:10.1523/JNEUROSCI.3519-06.2006.
- ^ Maximov A, Südhof TC (2005). "Autonomous function of synaptotagmin 1 in triggering synchronous release independent of asynchronous release". Neuron 48: 547–554. doi:10.1016/j.neuron.2005.09.006.
- ^ O'Connor V, Lee AG (2002). "Synaptic vesicle fusion and synaptotagmin: 2B or not 2B?". Nature Neuroscience 5: 823–824. doi:10.1038/nn0902-823.
- ^ 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. doi:10.1016/j.cell.2006.08.030.
- ^ Zimmerberg J, Akimov SA, Frolov V (2006). "Synaptotagmin: fusogenic role for calcium sensor?". Nature Structural & Molecular Biology 13: 301–303. doi:10.1038/nsmb0406-301.
- ^ 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. doi:10.1038/35065004.
- ^ Chapman ER (2002). "Synaptotagmin: A Ca2+ sensor that triggers exocytosis?". Nature Reviews Molecular Cell Biology 3: 498–508. doi:10.1038/nrm855.
[edit] External links
