Synaptotagmin rings as high-sensitivity regulators of synaptic vesicle docking and fusion

• DOI: 10.1073/pnas.2208337119
• Publication Date: 2022-09-14T18:07:18Z
• Authors: Jie Zhu; Zachary A. McDargh; Feng Li; Shyam S. Krishnak...; James E. Rothman; Ben O’Shaughnessy
• Keywords: Vesicle fusion; Synaptotagmin 1; Docking (animal); C2 domain; SNAP25; Kiss-and-run fusion

Synchronous release at neuronal synapses is accomplished by a machinery that senses calcium influx and fuses the synaptic vesicle plasma membranes to neurotransmitters. Previous studies suggested sensor synaptotagmin (Syt) facilitator of docking both inhibitor fusion. On phospholipid monolayers, Syt C2AB domain spontaneously oligomerized into rings are disassembled Ca 2+ , suggesting may clamp fusion as membrane-separating “washers” until -mediated disassembly triggers [J. Wang et al., Proc. Natl. Acad. Sci. U.S.A. 111, 13966–13971 (2014)].). Here, we combined mathematical modeling with experiment measure mechanical properties test this mechanism. Consistent experimental results, model quantitatively recapitulates observed ring-induced dome volcano shapes on monolayers predicts stabilized anionic bilayers or bulk solution ATP. The selected ring conformation highly sensitive membrane composition ATP levels, property regulate in ATP-rich terminals. We find molecules hosted oligomerize halo, unbound from vesicle, but proximity sufficiently phosphatidylinositol 4,5-bisphosphate (PIP2)-rich (PM) domains, PM-bound trans preferred. Thus, halo serves landing gear for spatially directed PIP2-rich sites define active zones exocytotic release, positioning await calcium. Our results suggest -sensitive high-fidelity docking.