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Title : The Cooperative Response of Synaptotagmin I C 2 A . A Hypothesis for a Ca 2 +-Driven Molecular

In the current understanding of exocytosis at the nerve terminal, the C2A domain of synaptotagmin is presumed to bind Ca and the membrane in a stepwise fashion: cation then membrane as cation increases the affinity of protein for membrane. Fluorescence spectroscopy data was gathered over a variety of lipid and Ca concentrations, enabling the rigorous application of microscopic binding models derived from partition functions to differentiate between Ca and phosphatidylserine (PS) contributions to binding. The present data is in variance with previously published models, which were based on the Hill approximation. Rather, it is consistent with two forms of cooperativity that modulate the responsiveness of C2A: in Ca binding to a network of three cation sites and in interaction with the membrane surface. We suggest synaptotagmin I C2A is preassociated with the synaptic vesicle membrane or nerve terminal. In this state, upon Ca influx the protein will bind the three Ca ions immediately and with high cooperativity. Thus, membrane association creates a high affinity Ca switch that is the basis for the role of synaptotagmin I in Ca-regulated exocytosis. Based on this model, we discuss the implications of protein-induced PS demixing to the exocytotic process.