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Phosphatidylinositol 4,5-bisphosphate clusters act as molecular beacons for vesicle recruitment

Synaptic vesicle exocytosis is mediated by the vesicular Ca(2+)-sensor synaptotagmin-1. Synaptotagmin-1 interacts with the SNARE protein syntaxin-1A and with acidic phospholipids such as phosphatidylinositol 4,5-bisphosphate (PIP2). However, it is unclear how these interactions contribute to trigger...

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Detalles Bibliográficos
Autores principales: Honigmann, Alf, van den Bogaart, Geert, Iraheta, Emilio, Risselada, H. Jelger, Milovanovic, Dragomir, Mueller, Veronika, Müllar, Stefan, Diederichsen, Ulf, Fasshauer, Dirk, Grubmüller, Helmut, Hell, Stefan W., Eggeling, Christian, Kühnel, Karin, Jahn, Reinhard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676452/
https://www.ncbi.nlm.nih.gov/pubmed/23665582
http://dx.doi.org/10.1038/nsmb.2570
Descripción
Sumario:Synaptic vesicle exocytosis is mediated by the vesicular Ca(2+)-sensor synaptotagmin-1. Synaptotagmin-1 interacts with the SNARE protein syntaxin-1A and with acidic phospholipids such as phosphatidylinositol 4,5-bisphosphate (PIP2). However, it is unclear how these interactions contribute to triggering membrane fusion. Using both PC12 cells from Rattus norvegicus and artificial supported bilayers we now show that synaptotagmin-1 interacts with the polybasic linker region of syntaxin-1A independent of Ca(2+) via PIP2. This interaction allows both Ca(2+)-binding sites of synaptotagmin-1 to bind to phosphatidylserine (PS) in the vesicle membrane upon Ca(2+)-triggering. We determined the crystal structure of the C2B-domain of synaptotagmin-1 bound to phosphoserine, allowing for developing 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.