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PMID: 23665582 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature structural & molecular biology ·Vol. 20 ·No. 6 ·2013-06-00 ·Pages 679-86

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

Abstract

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.

MeSH Terms
Animals Crystallography, X-Ray Exocytosis Models, Biological Models, Molecular PC12 Cells Phosphatidylinositol 4,5-Diphosphate/metabolism Protein Binding Protein Conformation Rats Synaptic Vesicles/metabolism Synaptotagmin I/chemistry,metabolism Syntaxin 1/metabolism
Chemicals
Phosphatidylinositol 4,5-Diphosphate Synaptotagmin I Syntaxin 1 Syt1 protein, rat
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Honigmann Alf
Department of Nanobiophotonics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
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
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Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9985
DOI
10.1038/nsmb.2570
Published
2013-06-00
Epub
2013-00-12
Pages
679-86
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC3676452
Subset
IM
Grants
Medical Research Council · MR/K01577X/1 · United Kingdom
NIGMS NIH HHS · P01 GM072694 · United States
Databases
PDB
2YOA
External Links
PubMed source DOI: 10.1038/nsmb.2570 PMC Full Text View journal details
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