Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming in C. elegans

ELife
Haowen LiuZhitao Hu

Abstract

UNC-13 proteins play an essential role in synaptic transmission by recruiting synaptic vesicles (SVs) to become available for release, which is termed SV priming. Here we show that the C2A domain of UNC-13L, like the corresponding domain in mammalian Munc13-1, displays two conserved binding modes: forming C2A/C2A homodimers, or forming a heterodimer with the zinc finger domain of UNC-10/RIM (C2A/RIM). Functional analysis revealed that UNC-13L's C2A promotes synaptic transmission by regulating a post-priming process. Stimulus-evoked release but not SV priming, was impaired in unc-10 mutants deficient for C2A/RIM heterodimerization, leading to decreased release probability. Disrupting C2A/C2A homodimerization in UNC-13L-rescued animals had no effect on synaptic transmission, but fully restored the evoked release and the release probability of unc-10/RIM mutants deficient for C2A/RIM heterodimerization. Thus, our results support the model that RIM binding C2A releases UNC-13L from an autoinhibitory homodimeric complex to become fusion-competent by functioning as a switch only.

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Citations

May 1, 2019·Cellular and Molecular Life Sciences : CMLS·Ardalan HendiKota Mizumoto
Feb 12, 2021·The Journal of Cell Biology·Lei LiZhitao Hu
Apr 11, 2021·Proceedings of the National Academy of Sciences of the United States of America·Murugesh PadmanarayanaJeremy S Dittman
Aug 24, 2021·Frontiers in Molecular Neuroscience·Chad W Sauvola, J Troy Littleton

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Methods Mentioned

BETA
transgenic
isothermal
co-immunoprecipitation
gel filtration
Isothermal titration calorimetry
PCR

Software Mentioned

Igor
Slidebook
Huygens Professional
ImageJ

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