Abstract
Synaptotagmins (Syts) are the primary Ca(2+)-sensors for synaptic vesicle exocytosis, while most mammalian Syts are non-Ca(2+)-affinitive and play critical roles in neurotransmission and synaptic plasticity with unclear mechanisms. Here, we show that high-alkaline non-Ca(2+)-binding Syt11 exhibits higher affinity for acidic phospholipids and Ca(2+)-inhibited liposome-binding, thereby competing with the Ca(2+)-binding Syt1. Physiological levels of Ca(2+) eliminate this competition by promoting Ca(2+)-dependent membrane insertion of Syt1 while suppressing Syt11's binding through electrostatic shielding of the membrane surface. Site-directed mutagenesis reveals a dual-regional lipid-binding mode (a lysine-rich motif for Ca(2+)-independent binding and Ca(2+)-binding loops for Ca(2+)-facilitation) for Syt1, and a redundant multi-point lipid-binding interface for Syt11. Consistent with the Ca(2+)-dependent competition, Syt11 inhibits both the early stages of exocytosis and endocytosis in neurons, while the maximal rate of exocytosis remains intact. This Ca(2+)-sensitivity of Syt11 proposes Syt1-Syt11 inter-switching in membrane-occupancy as a critical step precisely controlling exocytosis and endocytosis during synaptic transmission.