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Synaptic-vesicle exocytosis is mediated by the vesicular Ca(2+) sensor synaptotagmin-1. Synaptotagmin-1 interacts with the SNARE protein syntaxin-1A and acidic phospholipids such as phosphatidylinositol 4,5-bisphosphate (PIP2). However, it is unclear how these interactions contribute to triggering membrane fusion. Using PC12 cells from Rattus norvegicus and artificial supported bilayers, we show that synaptotagmin-1 interacts with the polybasic linker region of syntaxin-1A independent of Ca(2+) through PIP2. This interaction allows both Ca(2+)-binding sites of synaptotagmin-1 to bind to phosphatidylserine in the vesicle membrane upon Ca(2+) triggering. We determined the crystal structure of the C2B domain of synaptotagmin-1 bound to phosphoserine, allowing development of a high-resolution model of synaptotagmin bridging two different membranes. Our results suggest that PIP2 clusters organized by syntaxin-1 act as molecular beacons for vesicle docking, with the subsequent Ca(2+) influx bringing the vesicle membrane close enough for membrane fusion.

Original publication

DOI

10.1038/nsmb.2570

Type

Journal article

Journal

Nat Struct Mol Biol

Publication Date

06/2013

Volume

20

Pages

679 - 686

Keywords

Animals, Crystallography, X-Ray, Exocytosis, Models, Biological, Models, Molecular, PC12 Cells, Phosphatidylinositol 4,5-Diphosphate, Protein Binding, Protein Conformation, Rats, Synaptic Vesicles, Synaptotagmin I, Syntaxin 1