Architecture of the synaptotagmin-SNARE machinery for neuronal exocytosis.
Publication Type:Journal Article
Source:Nature, Volume 525, Issue 7567, p.62-7 (2015)
Keywords:Animals, Binding Sites, Calcium, Cell Membrane, Crystallography, X-Ray, Electrons, Exocytosis, Hippocampus, Lasers, Magnesium, Membrane Fusion, Mice, Models, Biological, Models, Molecular, Mutation, Neurons, SNARE Proteins, Synaptic Transmission, Synaptic Vesicles, Synaptotagmins
<p>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.</p>