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 a Ca²⁺ sensor and is involved in both:
* (i) early synaptic vesicle docking to the presynaptic membrane via interaction with β-neurexincite 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] or SNAP-25cite 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]
* (ii) late steps of Ca²⁺ evoked synaptic vesicle fusion with the presynaptic membrane.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 Ca²⁺ 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] 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] 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] 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.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]

C-terminal C2-domains

The C2A domain regulates the fusion step of synaptic vesicle exocytosis.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] 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] 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).cite journal
author = Chapman ER
url = http://www.physiology.wisc.edu/chapman/papers/naturereview.pdf
title = Synaptotagmin: A Ca²⁺ sensor that triggers exocytosis?
journal = Nature Reviews Molecular Cell Biology
volume = 3
pages = 498–508
year = 2002
doi = 10.1038/nrm855] 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

External links

* - Orientations of C2 domains in the lipid bilayer
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