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A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusion
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A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusion
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A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusion
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Journal Article
A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusion
2011
Overview
Comparison of the prefusion and postfusion structures of complexin associated with SNAREs reveals a conformational switch in complexin, which is triggered by the zippering of three key Asp residues in the “switch” region of v-SNAREs into t-SNAREs. This causes complexin to move its accessory helix, thereby releasing the clamped state. This switch is triggered when the calcium sensor synaptotagmin binds calcium ions.
The crystal structure of complexin bound to a prefusion SNAREpin mimetic shows that the accessory helix extends away from the SNAREpin in an 'open' conformation, binding another SNAREpin and inhibiting its assembly, to clamp fusion. In contrast, the accessory helix in the postfusion complex parallels the SNARE complex in a 'closed' conformation. Here we use targeted mutations, FRET spectroscopy and a functional assay that reconstitutes Ca
2+
-triggered exocytosis to show that the conformational switch from open to closed in complexin is needed for synaptotagmin-Ca
2+
to trigger fusion. Triggering fusion requires the zippering of three crucial aspartate residues in the switch region (residues 64–68) of v-SNARE. Conformational switching in complexin is integral to clamp release and is probably triggered when its accessory helix is released from its
trans
-binding to the neighboring SNAREpin, allowing the v-SNARE to complete zippering and open a fusion pore.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Adaptor Proteins, Vesicular Transport - chemistry
/ Adaptor Proteins, Vesicular Transport - metabolism
/ Adaptor Proteins, Vesicular Transport - physiology
/ Animals
/ Biomedical and Life Sciences
/ Humans
/ Membrane Fusion - physiology
/ Mutation
/ Nerve Tissue Proteins - chemistry
/ Nerve Tissue Proteins - metabolism
/ Nerve Tissue Proteins - physiology
/ Proteins
/ Rats
/ Residues
/ Synaptosomal-Associated Protein 25 - chemistry
/ Synaptosomal-Associated Protein 25 - metabolism
/ Vesicle-Associated Membrane Protein 2 - chemistry
