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Architecture of the synaptotagmin-SNARE machinery for neuronal exocytosis.

Zhou Q., Lai Y., Bacaj T., Zhao M., Lyubimov A.Y., Uervirojnangkoorn M., Zeldin O.B., Brewster A.S., Sauter N.K., Cohen A.E., Soltis S.M., Alonso-Mori R., Chollet M., Lemke H.T., Pfuetzner R.A., Choi U.B., Weis W.I., Diao J., Suedhof T.C., Brunger A.T.

Synaptotagmin-1 and neuronal SNARE proteins have central roles in evoked synchronous neurotransmitter release; however, it is unknown how they cooperate to trigger synaptic vesicle fusion. Here we report atomic-resolution crystal structures of Ca(2+)- and Mg(2+)-bound complexes between synaptotagmin-1 and the neuronal SNARE complex, one of which was determined with diffraction data from an X-ray free-electron laser, leading to an atomic-resolution structure with accurate rotamer assignments for many side chains. The structures reveal several interfaces, including a large, specific, Ca(2+)-independent and conserved interface. Tests of this interface by mutagenesis suggest that it is essential for Ca(2+)-triggered neurotransmitter release in mouse hippocampal neuronal synapses and for Ca(2+)-triggered vesicle fusion in a reconstituted system. We propose that this interface forms before Ca(2+) triggering, moves en bloc as Ca(2+) influx promotes the interactions between synaptotagmin-1 and the plasma membrane, and consequently remodels the membrane to promote fusion, possibly in conjunction with other interfaces.

Nature 525:62-67(2015) [PubMed] [Europe PMC]

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