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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.

Author information

1
Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.
2
Departments of Neurology and Neurological Sciences, Photon Science, and Structural Biology, Stanford University, Stanford, California 94305, USA.
3
Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
4
SLAC National Accelerator Laboratory, Stanford, California 94305, USA.
5
Departments of Structural Biology, Molecular and Cellular Physiology, and Photon Science, Stanford University, Stanford, California 94305, USA.

Abstract

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.

PMID:
26280336
PMCID:
PMC4607316
DOI:
10.1038/nature14975
[Indexed for MEDLINE]
Free PMC Article

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