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Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):13966-71. doi: 10.1073/pnas.1415849111. Epub 2014 Sep 8.

Calcium sensitive ring-like oligomers formed by synaptotagmin.

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Departments of Cell Biology.
Chemistry, and.
Departments of Cell Biology, Laboratoire de Physique Statistique, Unité Mixte de Recherche, Centre National de la Recherche Scientifique, 8550 Associée aux Universités Paris 6 et Paris 7, Ecole Normale Supérieure, 75005 Paris, France.
Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520; and
Departments of Cell Biology, Chemistry, and


The synaptic vesicle protein synaptotagmin-1 (SYT) is required to couple calcium influx to the membrane fusion machinery. However, the structural mechanism underlying this process is unclear. Here we report an unexpected circular arrangement (ring) of SYT's cytosolic domain (C2AB) formed on lipid monolayers in the absence of free calcium ions as revealed by electron microscopy. Rings vary in diameter from 18-43 nm, corresponding to 11-26 molecules of SYT. Continuous stacking of the SYT rings occasionally converts both lipid monolayers and bilayers into protein-coated tubes. Helical reconstruction of the SYT tubes shows that one of the C2 domains (most likely C2B, based on its biochemical properties) interacts with the membrane and is involved in ring formation, and the other C2 domain points radially outward. SYT rings are disrupted rapidly by physiological concentrations of free calcium but not by magnesium. Assuming that calcium-free SYT rings are physiologically relevant, these results suggest a simple and novel mechanism by which SYT regulates neurotransmitter release: The ring acts as a spacer to prevent the completion of the soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) complex assembly, thereby clamping fusion in the absence of calcium. When the ring disassembles in the presence of calcium, fusion proceeds unimpeded.

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