Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 20, Issue 6, Pages 679-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2570
Keywords
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Funding
- Human Frontier Science Program
- US National Institutes of Health [P01 GM072694]
- Deutsche Forschungsgemeinschaft [SFB803]
- Medical Research Council [MR/K01577X/1, MC_UU_12010/9] Funding Source: researchfish
- MRC [MR/K01577X/1, MC_UU_12010/9] Funding Source: UKRI
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Synaptic-vesicle exocytosis is mediated by the vesicular Ca2+ 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 Ca2+ through PIP2. This interaction allows both Ca2+-binding sites of synaptotagmin-1 to bind to phosphatidylserine in the vesicle membrane upon Ca2+ 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 Ca2+ influx bringing the vesicle membrane close enough for membrane fusion.
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