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Domain Structure of synaptotagmin-1

What are synaptotagmins? The synaptotagmins are a family of proteins with an N-terminal transmembrane domain and two cytoplasmic C2 domains (see family members). Many C2 domains mediate calcium-dependent binding to negatively charged membranes. Synaptotagmin-1 is localized to synaptic vesicles and is the trigger for their calcium-induced exocytosis. The two C2 domains of synaptotagmin-1 insert into the membrane upon calcium binding.

C2 domain structure showing hydrophobic residues on loops

How do we think synaptotagmin-1 induces membrane fusion? When bound to calcium the two C2 domains insert into the membrane (see model). Shallow insertions into the membrane cause the induction of positive membrane curvature seen as tubulation (see epsin1 pages). We proposed that synaptotagmin promotes synaptic vesicle insertion by the local buckling of the plasma membrane under the synaptic vesicle which is tethered to the plasma membrane by the SNARE complex. The synaptotagmin-1 induced buckling of the plasma membrane brings the two membranes destined to fuse into close proximity and further induces curvature stress in the buckle end cap. Both effects will strongly increase the probability of membrane fusion.

Vesicle fusion proceeds via plasma membrane buckling induced by insertion of hydrophobic residues from synaptotagmin into the plasma membrane

Calculation: A 17nm dimple will reduce the energy for hemifusion stalk formation from 40kBT to 20kBT

How do synaptotagmins and SNARE proteins work together? SNARE proteins contain motifs that fold into a stable 4 helix bundle pulling the vesicle into close proximity with the plasma membrane (as seen in the pictures below).

1. Vesicle meets cognate membrane
SNARE protein assembly

2. SNAREs engage
SNARE assmebly2

3. SNARE complexes form, and with synaptotagmin membranes undergo fusion via a high curvature intermediate
SNARE assembly3
Click here for a movie of SNARE assembly

Further questions and outlook:
We have shown that other synaptotagmin-related double C2 domain containing proteins (synaptotagmin-3, -9 and synaptotagmin-like protein 2) also induce membrane curvature. Do these molecules function analogous to synaptotagmin-1 in other membrane fusion events?

We have shown that the double C2 domain module of synaptotagmin-1 is required for the induction of membrane curvature. Why don’t the isolated C2 domains of synaptotagmin-1 induce membrane curvature?

Most intracellular membrane fusion events are SNARE-dependent. Do these membrane fusion events also require accessory molecules that function similar to synaptotagmin-1 during synaptic vesicle exocytosis?

Our publications on synaptotagmin
Martens et al Science 2007
Martens and McMahon Nature reviews 2008
Lynch et al MBC 2008
Groffen et al Science 2010
McMahon et al Cell 2010

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