Phosphatidylinositol 4,5-bisphosphate clusters act as molecular beacons for vesicle recruitment
Authors: Honigmann A, van den Bogaart G, Iraheta E, Risselada HJ, Milovanovic D, Mueller V, Müllar S, Diederichsen U, Fasshauer D, Grubmüller H, Hell SW, Eggeling C, Kühnel K, Jahn R
CellNetworks People: Hell Stefan
Journal: Nat Struct Mol Biol. 2013 Jun;20(6):679-86. doi: 10.1038/nsmb.2570

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.