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Synaptic vesicle fusion is mediated by SNARE proteins-VAMP2 on the vesicle and Syntaxin-1/SNAP25 on the presynaptic membrane. Chaperones Munc18-1 and Munc13-1 cooperatively catalyze SNARE assembly via an intermediate 'template' complex containing Syntaxin-1 and VAMP2. How SNAP25 enters this reaction remains a mystery. Here, we report that Munc13-1 recruits SNAP25 to initiate the ternary SNARE complex assembly by direct binding, as judged by bulk FRET spectroscopy and single-molecule optical tweezer studies. Detailed structure-function analyses show that the binding is mediated by the Munc13-1 MUN domain and is specific for the SNAP25 'linker' region that connects the two SNARE motifs. Consequently, freely diffusing SNAP25 molecules on phospholipid bilayers are concentrated and bound in ~ 1 : 1 stoichiometry by the self-assembled Munc13-1 nanoclusters. © 2020 Federation of European Biochemical Societies.


Ramalingam Venkat Kalyana Sundaram, Huaizhou Jin, Feng Li, Tong Shu, Jeff Coleman, Jie Yang, Frederic Pincet, Yongli Zhang, James E Rothman, Shyam S Krishnakumar. Munc13 binds and recruits SNAP25 to chaperone SNARE complex assembly. FEBS letters. 2021 Feb;595(3):297-309

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PMID: 33222163

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