Munc18-1 binding to the neuronal SNARE complex controls synaptic vesicle priming

Ferenc Deàk, Yi Xu, Wen Pin Chang, Irina Dulubova, Mikhail Khvotchev, Xinran Liu, Thomas C. Südhof, Josep Rizo

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

Abstract

Munc18-1 and soluble NSF attachment protein receptors (SNAREs) are critical for synaptic vesicle fusion. Munc18-1 binds to the SNARE syntaxin-1 folded into a closed conformation and to SNARE complexes containing open syntaxin-1. Understanding which steps in fusion depend on the latter interaction and whether Munc18-1 competes with other factors such as complexins for SNARE complex binding is critical to elucidate the mechanisms involved. In this study, we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice. We describe point mutations in Munc18-1 that preserve tight binding to closed syntaxin-1 but markedly disrupt Munc18-1 binding to SNARE complexes containing open syntaxin-1. Lentiviral rescue experiments reveal that such disruption selectively impairs synaptic vesicle priming but not Ca2+ -triggered fusion of primed vesicles. We also find that Munc18-1 and complexin-1 bind simultaneously to SNARE complexes. These results suggest that Munc18-1 binding to SNARE complexes mediates synaptic vesicle priming and that the resulting primed state involves a Munc18-1 - SNARE - complexin macromolecular assembly that is poised for Ca2+ triggering of fusion.

Original languageEnglish (US)
Pages (from-to)751-764
Number of pages14
JournalJournal of Cell Biology
Volume184
Issue number5
DOIs
StatePublished - Mar 9 2009

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'Munc18-1 binding to the neuronal SNARE complex controls synaptic vesicle priming'. Together they form a unique fingerprint.

Cite this