Membrane bridging by Munc13-1 is crucial for neurotransmitter release

ELife
Bradley QuadeJosep Rizo

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.

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Citations

May 6, 2019·International Journal of Molecular Sciences·Rituparna Chakrabarti, Carolin Wichmann
Sep 25, 2019·Nature Communications·Karolina P StepienJosep Rizo
Feb 23, 2020·Protein Science : a Publication of the Protein Society·Magdalena MagdziarekJosep Rizo
May 20, 2020·Alcoholism, Clinical and Experimental Research·Youngki You, Joydip Das
Sep 12, 2020·Journal of Neurochemistry·Holly MellandSarah L Gordon
Jan 1, 2020·Proceedings of the National Academy of Sciences of the United States of America·Tong ShuYongli Zhang
Jun 27, 2019·Proceedings of the National Academy of Sciences of the United States of America·Hongki Song, William Wickner
Nov 23, 2020·FEBS Letters·Ramalingam Venkat Kalyana SundaramShyam S Krishnakumar
Jan 21, 2021·Proceedings of the National Academy of Sciences of the United States of America·Karolina P Stepien, Josep Rizo
Nov 4, 2020·Nature Communications·Chi-Wei TienShuzo Sugita
Feb 2, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Feng ChenYan Wang
Apr 6, 2021·Biochemistry·Youngki YouJoydip Das
Apr 11, 2021·Proceedings of the National Academy of Sciences of the United States of America·Murugesh PadmanarayanaJeremy S Dittman
May 30, 2021·Trends in Neurosciences·Melissa SilvaAlain Marty
Apr 8, 2021·Annual Review of Biochemistry·Yongli Zhang, Frederick M Hughson
Aug 21, 2021·Proceedings of the National Academy of Sciences of the United States of America·Rohith K NellikkaDebasis Das
Nov 16, 2021·Journal of Biomolecular Structure & Dynamics·Youngki You, Joydip Das

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Methods Mentioned

BETA
two-hybrid
NMR
Fluorescence
dynamic light scattering
FRET
electron tomography
pulldown
PCR
transmission
ICE

Software Mentioned

Clampex
SerialEM
SWISS
Matlab scripts
AxoGraph X
NMR View
IMOD
ImageJ
MODEL
Leica Application Suite X ( LAsX )

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