Open AccessA unique C2 domain at the C terminus of Munc13 promotes synaptic vesicle priming
Author(s) -
Murugesh Padmanarayana,
Haowen Liu,
Francesco Michelassi,
Lei Li,
Daniel Betensky,
Matthew J. Dominguez,
R. Bryan Sutton,
Zhitao Hu,
Jeremy S. Dittman
Publication year - 2021
Publication title -
proceedings of the national academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2016276118
Subject(s) - synaptic vesicle , microbiology and biotechnology , neurotransmission , vesicle fusion , caenorhabditis elegans , biology , vesicle , kiss and run fusion , neurotransmitter , endosome , signal transducing adaptor protein , c2 domain , snap25 , fusion protein , biochemistry , signal transduction , membrane , gene , receptor , recombinant dna , intracellular
Neurotransmitter release during synaptic transmission comprises a tightly orchestrated sequence of molecular events, and Munc13-1 is a cornerstone of the fusion machinery. A forward genetic screen for defects in neurotransmitter release in Caenorhabditis elegans identified a mutation in the Munc13-1 ortholog UNC-13 that eliminated its unique and deeply conserved C-terminal module (referred to as HC2M) containing a Ca 2+ -insensitive C2 domain flanked by membrane-binding helices. The HC2M module could be functionally replaced in vivo by protein domains that localize to synaptic vesicles but not to the plasma membrane. HC2M is broadly conserved in other Unc13 family members and is required for efficient synaptic vesicle priming. We propose that the HC2M domain evolved as a vesicle/endosome adaptor and acquired synaptic vesicle specificity in the Unc13ABC protein family.
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