Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520, USA; email:
Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA; email:
Annu Rev Biochem. 2021 Jun 20;90:581-603. doi: 10.1146/annurev-biochem-081820-103615. Epub 2021 Apr 6.
SNARE proteins and Sec1/Munc18 (SM) proteins constitute the core molecular engine that drives nearly all intracellular membrane fusion and exocytosis. While SNAREs are known to couple their folding and assembly to membrane fusion, the physiological pathways of SNARE assembly and the mechanistic roles of SM proteins have long been enigmatic. Here, we review recent advances in understanding the SNARE-SM fusion machinery with an emphasis on biochemical and biophysical studies of proteins that mediate synaptic vesicle fusion. We begin by discussing the energetics, pathways, and kinetics of SNARE folding and assembly in vitro. Then, we describe diverse interactions between SM and SNARE proteins and their potential impact on SNARE assembly in vivo. Recent work provides strong support for the idea that SM proteins function as chaperones, their essential role being to enable fast, accurate SNARE assembly. Finally, we review the evidence that SM proteins collaborate with other SNARE chaperones, especially Munc13-1, and briefly discuss some roles of SNARE and SM protein deficiencies in human disease.
SNARE 蛋白和 Sec1/Munc18（SM）蛋白构成了驱动几乎所有细胞内膜融合和胞吐作用的核心分子引擎。虽然 SNARE 蛋白的折叠和组装与膜融合有关，但 SNARE 组装的生理途径和 SM 蛋白的机械作用长期以来一直是个谜。在这里，我们综述了近年来对 SNARE-SM 融合机制的理解进展，重点介绍了介导突触囊泡融合的蛋白质的生化和生物物理研究。我们首先讨论 SNARE 体外折叠和组装的能量学、途径和动力学。然后，我们描述了 SM 和 SNARE 蛋白之间的多种相互作用及其对体内 SNARE 组装的潜在影响。最近的工作为 SM 蛋白作为分子伴侣发挥作用的观点提供了强有力的支持，其核心作用是使 SNARE 快速、准确地组装。最后，我们综述了 SM 蛋白与其他 SNARE 伴侣，特别是 Munc13-1 协作的证据，并简要讨论了 SNARE 和 SM 蛋白缺陷在人类疾病中的一些作用。
