Munc13 通过结合 SNAP25 将 SNARE 复合物募集到分子伴侣上。
Munc13 binds and recruits SNAP25 to chaperone SNARE complex assembly.
机构信息
Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
Laboratoire de Physique de Ecole Normale Supérieure, Université PSL, CNRS, Sorbonne Université, Université de Paris 06, Paris, France.
出版信息
FEBS Lett. 2021 Feb;595(3):297-309. doi: 10.1002/1873-3468.14006. Epub 2020 Dec 5.
Abstract
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.
摘要
突触小泡融合由 SNARE 蛋白介导 - 囊泡上的 VAMP2 和突触前膜上的 Syntaxin-1/SNAP25。伴侣蛋白 Munc18-1 和 Munc13-1 通过含有 Syntaxin-1 和 VAMP2 的中间“模板”复合物协同催化 SNARE 组装。SNAP25 如何进入该反应仍然是一个谜。在这里，我们报告 Munc13-1 通过直接结合招募 SNAP25 以启动三元 SNARE 复合物组装，这可以通过 bulk FRET 光谱和单分子光镊研究来判断。详细的结构功能分析表明，结合是由 Munc13-1 的 MUN 结构域介导的，并且特异性针对连接两个 SNARE 基序的 SNAP25“连接区”。因此，在磷脂双层上自由扩散的 SNAP25 分子通过自组装的 Munc13-1 纳米簇以 ~1：1 的化学计量比浓缩和结合。
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