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Synaptotagmin 1 clamps synaptic vesicle fusion in mammalian neurons independent of complexin.

ABSTRACT: Synaptic vesicle (SV) exocytosis is mediated by SNARE proteins. Reconstituted SNAREs are constitutively active, so a major focus has been to identify fusion clamps that regulate their activity in synapses: the primary candidates are synaptotagmin (syt) 1 and complexin I/II. Syt1 is a Ca²⁺ sensor for SV release that binds Ca²⁺ via tandem C2-domains, C2A and C2B. Here, we first determined whether these C2-domains execute distinct functions. Remarkably, the C2B domain profoundly clamped all forms of SV fusion, despite synchronizing residual evoked release and rescuing the readily-releasable pool. Release was strongly enhanced by an adjacent C2A domain, and by the concurrent binding of complexin to trans-SNARE complexes. Knockdown of complexin had no impact on C2B-mediated clamping of fusion. We postulate that the C2B domain of syt1, independent of complexin, is the molecular clamp that arrests SVs prior to Ca²⁺-triggered fusion.

SUBMITTER: Courtney NA

PROVIDER: S-EPMC6733930 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Synaptotagmin 1 clamps synaptic vesicle fusion in mammalian neurons independent of complexin.

Courtney Nicholas A NA Bao Huan H Briguglio Joseph S JS Chapman Edwin R ER

Nature communications 20190909 1

Synaptic vesicle (SV) exocytosis is mediated by SNARE proteins. Reconstituted SNAREs are constitutively active, so a major focus has been to identify fusion clamps that regulate their activity in synapses: the primary candidates are synaptotagmin (syt) 1 and complexin I/II. Syt1 is a Ca<sup>2+</sup> sensor for SV release that binds Ca<sup>2+</sup> via tandem C2-domains, C2A and C2B. Here, we first determined whether these C2-domains execute distinct functions. Remarkably, the C2B domain profound ...[more]

PMID: 31501440

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