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

Ferenc Deák, Y. Xu, Wen Pin Chang, Irina Dulubova, Mikhail Khvotchev, Xinran Liu, Thomas C. Südhof, Jose Rizo-Rey

Research output: Contribution to journalArticle

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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 Ca(2+)-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 Ca(2+) triggering of fusion.

Original languageEnglish (US)
Pages (from-to)751-764
Number of pages14
JournalThe Journal of cell biology
Volume184
Issue number5
DOIs
StatePublished - Mar 9 2009

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Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins
SNARE Proteins
Synaptic Vesicles
Syntaxin 1
Point Mutation
Knockout Mice

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Munc18-1 binding to the neuronal SNARE complex controls synaptic vesicle priming. / Deák, Ferenc; Xu, Y.; Chang, Wen Pin; Dulubova, Irina; Khvotchev, Mikhail; Liu, Xinran; Südhof, Thomas C.; Rizo-Rey, Jose.

In: The Journal of cell biology, Vol. 184, No. 5, 09.03.2009, p. 751-764.

Research output: Contribution to journalArticle

Deák, F, Xu, Y, Chang, WP, Dulubova, I, Khvotchev, M, Liu, X, Südhof, TC & Rizo-Rey, J 2009, 'Munc18-1 binding to the neuronal SNARE complex controls synaptic vesicle priming.', The Journal of cell biology, vol. 184, no. 5, pp. 751-764. https://doi.org/10.1083/jcb.200812026
Deák, Ferenc ; Xu, Y. ; Chang, Wen Pin ; Dulubova, Irina ; Khvotchev, Mikhail ; Liu, Xinran ; Südhof, Thomas C. ; Rizo-Rey, Jose. / Munc18-1 binding to the neuronal SNARE complex controls synaptic vesicle priming. In: The Journal of cell biology. 2009 ; Vol. 184, No. 5. pp. 751-764.
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