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Munc18-1 诱导突触融合蛋白 1 在 SNARE 组装的多个中间产物中发生构象变化。

Munc18-1 induces conformational changes of syntaxin-1 in multiple intermediates for SNARE assembly.

机构信息

Advanced Photonics Research Institute, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea.

Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

出版信息

Sci Rep. 2020 Jul 15;10(1):11623. doi: 10.1038/s41598-020-68476-3.

DOI:10.1038/s41598-020-68476-3
PMID:32669573
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7363831/
Abstract

In neuronal exocytosis, SNARE assembly into a stable four-helix bundle drives membrane fusion. Previous studies have revealed that the SM protein Munc18-1 plays a critical role for precise SNARE assembly with the help of Munc13-1, but the underlying mechanism remains unclear. Here, we used single-molecule FRET assays with a nanodisc membrane reconstitution system to investigate the conformational dynamics of SNARE/Munc18-1 complexes in multiple intermediate steps towards the SNARE complex. We found that single Munc18-1 proteins induce the closed conformation of syntaxin-1 not only in the free syntaxin-1 but also in the t-SNARE (syntaxin-1/SNAP-25) complex. These results implicate that Munc18-1 may act as a gatekeeper for both binary and ternary SNARE complex formation by locking the syntaxin-1 in a cleft of Munc18-1. Furthermore, the kinetic analysis of the opening/closing transition reveals that the closed syntaxin-1 in the syntaxin-1/SNAP-25/Munc18-1 complex is less stable than that in the closed syntaxin-1/Munc18-1 complex, which is manifested by the infrequent closing transition, indicating that the conformational equilibrium of the ternary complex is biased toward the open conformation of syntaxin-1 compared with the binary complex.

摘要

在神经元胞吐作用中，SNARE 组装成稳定的四螺旋束驱动膜融合。先前的研究表明，SM 蛋白 Munc18-1 在 Munc13-1 的帮助下对于精确的 SNARE 组装起着关键作用，但潜在的机制仍不清楚。在这里，我们使用带有纳米盘膜重组系统的单分子 FRET 测定法来研究 SNARE/Munc18-1 复合物在朝向 SNARE 复合物的多个中间步骤中的构象动力学。我们发现，单个 Munc18-1 蛋白不仅诱导游离突触素-1中的封闭构象，而且还诱导 t-SNARE（突触素-1/SNAP-25）复合物中的封闭构象。这些结果表明，Munc18-1 可能通过将突触素-1锁定在 Munc18-1 的裂隙中来充当二元和三元 SNARE 复合物形成的守门员。此外，对开闭转换的动力学分析表明，与封闭的突触素-1/Munc18-1 复合物相比，突触素-1/SNAP-25/Munc18-1 复合物中的封闭突触素-1不太稳定，这表现为闭合转换的频率较低，表明三元复合物的构象平衡相对于二元复合物偏向于突触素-1的开放构象。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f200/7363831/08d542d12e30/41598_2020_68476_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f200/7363831/3afef21b218b/41598_2020_68476_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f200/7363831/4b6347a14c11/41598_2020_68476_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f200/7363831/b6ecc48b0de5/41598_2020_68476_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f200/7363831/08d542d12e30/41598_2020_68476_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f200/7363831/3afef21b218b/41598_2020_68476_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f200/7363831/4b6347a14c11/41598_2020_68476_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f200/7363831/b6ecc48b0de5/41598_2020_68476_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f200/7363831/08d542d12e30/41598_2020_68476_Fig4_HTML.jpg

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