Complexin cross-links pre-fusion SNAREs into a zig-zag array: a structure-based model for complexin clamping

Complexin prevents SNAREs from releasing neurotransmitters until an action potential arrives at the synapse. To understand the mechanism for this inhibition, we determined the structure of complexin bound to a mimetic of a pre-fusion SNAREpin lacking the portion of the v-SNARE which zippers last to trigger fusion. The “central helix” of complexin is anchored to one SNARE complex while its “accessory helix” extends away at ~45° and bridges to a second complex, occupying the vacant v-SNARE binding site to inhibit fusion. That the accessory helix competes with the v-SNARE for t-SNARE binding was expected, but surprisingly, the interaction occurs inter-molecularly. Thus complexin organizes the SNAREs into a zig-zag topology which, when interposed between the vesicle and plasma membranes, is incompatible with fusion.