Synaptotagmin-1 drives synchronous Ca2+ triggered fusion by C2B domain-mediated synaptic vesicle-membrane attachment

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Abstract The synaptic vesicle (SV) protein Synaptotagmin-1 (Syt1) is the Ca2+ sensor for fast synchronous release. Biochemical and structural data suggest that Syt1 interacts with phospholipids and SNARE complex, but how these interactions translate into SV fusion remains poorly understood. Utilizing flash-and-freeze electron microscopy, which triggers action potentials (AP) with light and coordinately arrests synaptic structures with rapid freezing, we found synchronous release-impairing mutations in the Syt1 C2B domain (K325, 327; R398, 399) to also disrupt SV-active zone plasma membrane attachment. Single AP induction rescued membrane attachment in these mutants within <10ms through activation of the Syt1 Ca2+ binding site. The rapid SV membrane translocation temporarily correlates with resynchronization of release and paired pulse facilitation. Based on these findings, we redefine the role of Syt1 as part of Ca2+-dependent vesicle translocation machinery, and propose that Syt1 enables fast neurotransmitter release by means of its dynamic membrane attachment activities.