CAPS 囊泡相关蛋白结合结构域的结构与功能分析：SNARE 复合物形成与胞吐作用所必需。
Structural and Functional Analysis of the CAPS SNARE-Binding Domain Required for SNARE Complex Formation and Exocytosis.
机构信息
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, China.
National Center for Protein Science, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Science, Chinese Academy of Sciences, 201203 Shanghai, China.
出版信息
Cell Rep. 2019 Mar 19;26(12):3347-3359.e6. doi: 10.1016/j.celrep.2019.02.064.
Exocytosis of synaptic vesicles and dense-core vesicles requires both the Munc13 and CAPS (Ca-dependent activator proteins for secretion) proteins. CAPS contains a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-binding region (called the DAMH domain), which has been found to be essential for SNARE-mediated exocytosis. Here we report a crystal structure of the CAPS-1 DAMH domain at 2.9-Å resolution and reveal a dual role of CAPS-1 in SNARE complex formation. CAPS-1 plays an inhibitory role dependent on binding of the DAMH domain to the MUN domain of Munc13-1, which hinders the ability of Munc13 to catalyze opening of syntaxin-1, inhibiting SNARE complex formation, and a chaperone role dependent on interaction of the DAMH domain with the syntaxin-1/SNAP-25 complex, which stabilizes the open conformation of Syx1, facilitating SNARE complex formation. Our results suggest that CAPS-1 facilitates SNARE complex formation via the DAMH domain in a manner dependent on sequential and cooperative interaction with Munc13-1 and SNARE proteins.
囊泡胞吐作用需要 Munc13 和 CAPS（Ca 依赖性分泌激活蛋白）蛋白。CAPS 包含一个可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）结合区（称为 DAMH 结构域），该结构域对于 SNARE 介导的胞吐作用至关重要。在此，我们报告了 CAPS-1 DAMH 结构域的晶体结构，分辨率为 2.9 Å，并揭示了 CAPS-1 在 SNARE 复合物形成中的双重作用。CAPS-1 通过 DAMH 结构域与 Munc13-1 的 MUN 结构域的结合发挥抑制作用，从而阻碍 Munc13 催化突触融合蛋白 1（Syntaxin-1）的开放，抑制 SNARE 复合物的形成，以及依赖于 DAMH 结构域与突触融合蛋白 1/SNAP-25 复合物的相互作用的伴侣作用，稳定 Syx1 的开放构象，促进 SNARE 复合物的形成。我们的结果表明，CAPS-1 通过 DAMH 结构域以依赖于与 Munc13-1 和 SNARE 蛋白的顺序和协同相互作用的方式促进 SNARE 复合物的形成。
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