Membrane bridging by Munc13-1 is crucial for neurotransmitter release

Bradley Quade, Marcial Camacho, Xiaowei Zhao, Marta Orlando, Thorsten Trimbuch, Junjie Xu, Wei Li, Daniela Nicastro, Christian Rosenmund, Jose Rizo-Rey

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Munc13-1 plays a crucial role in neurotransmitter release. We recently proposed that the C-terminal region encompassing the C1, C2B, MUN and C2C domains of Munc13-1 (C1C2BMUNC2C) bridges the synaptic vesicle and plasma membranes through interactions involving the C2C domain and the C1-C2B region. However, the physiological relevance of this model has not been demonstrated. Here we show that C1C2BMUNC2C bridges membranes through opposite ends of its elongated structure. Mutations in putative membrane-binding sites of the C2C domain disrupt the ability of C1C2BMUNC2C to bridge liposomes and to mediate liposome fusion in vitro. These mutations lead to corresponding disruptive effects on synaptic vesicle docking, priming, and Ca2+-triggered neurotransmitter release in mouse neurons. Remarkably, these effects include an almost complete abrogation of release by a single residue substitution in this 200 kDa protein. These results show that bridging the synaptic vesicle and plasma membranes is a central function of Munc13-1.

Original languageEnglish (US)
JournaleLife
Volume8
DOIs
Publication statusPublished - Feb 28 2019

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Keywords

  • membrane bridging
  • molecular biophysics
  • mouse
  • Munc13
  • neuroscience
  • neurotransmitter release
  • reconstitution
  • structural biology
  • synaptic vesicle docking
  • synaptic vesicle fusion

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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