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Nature. 2015 Sep 3;525(7567):62-7. doi: 10.1038/nature14975. Epub 2015 Aug 17.

Architecture of the synaptotagmin-SNARE machinery for neuronal exocytosis.

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Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.
Departments of Neurology and Neurological Sciences, Photon Science, and Structural Biology, Stanford University, Stanford, California 94305, USA.
Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
SLAC National Accelerator Laboratory, Stanford, California 94305, USA.
Departments of Structural Biology, Molecular and Cellular Physiology, and Photon Science, Stanford University, Stanford, California 94305, USA.


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.

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