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

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: f...

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Autores principales: Liu, Haowen, Li, Lei, Nedelcu, Daniel, Hall, Qi, Zhou, Lijun, Wang, Wei, Yu, Yi, Kaplan, Joshua M, Hu, Zhitao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389284/
https://www.ncbi.nlm.nih.gov/pubmed/30802206
http://dx.doi.org/10.7554/eLife.40585
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author Liu, Haowen
Li, Lei
Nedelcu, Daniel
Hall, Qi
Zhou, Lijun
Wang, Wei
Yu, Yi
Kaplan, Joshua M
Hu, Zhitao
author_facet Liu, Haowen
Li, Lei
Nedelcu, Daniel
Hall, Qi
Zhou, Lijun
Wang, Wei
Yu, Yi
Kaplan, Joshua M
Hu, Zhitao
author_sort Liu, Haowen
collection PubMed
description 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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spelling pubmed-63892842019-02-27 Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming in C. elegans Liu, Haowen Li, Lei Nedelcu, Daniel Hall, Qi Zhou, Lijun Wang, Wei Yu, Yi Kaplan, Joshua M Hu, Zhitao eLife Neuroscience 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. eLife Sciences Publications, Ltd 2019-02-25 /pmc/articles/PMC6389284/ /pubmed/30802206 http://dx.doi.org/10.7554/eLife.40585 Text en © 2019, Liu et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Liu, Haowen
Li, Lei
Nedelcu, Daniel
Hall, Qi
Zhou, Lijun
Wang, Wei
Yu, Yi
Kaplan, Joshua M
Hu, Zhitao
Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming in C. elegans
title Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming in C. elegans
title_full Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming in C. elegans
title_fullStr Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming in C. elegans
title_full_unstemmed Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming in C. elegans
title_short Heterodimerization of UNC-13/RIM regulates synaptic vesicle release probability but not priming in C. elegans
title_sort heterodimerization of unc-13/rim regulates synaptic vesicle release probability but not priming in c. elegans
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389284/
https://www.ncbi.nlm.nih.gov/pubmed/30802206
http://dx.doi.org/10.7554/eLife.40585
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