Zippering of SNARE complexes spanning docked membranes is essential for most intracellular fusion events. Here, we explore how SNARE regulators operate on discrete zippering states. The formation of a metastable trans-complex, catalyzed by HOPS and its SM subunit Vps33, is followed by subsequent zippering transitions that increase the probability of fusion. Operating independently of Sec18 (NSF) catalysis, Sec17 (α-SNAP) either inhibits or stimulates SNARE-mediated fusion. If HOPS or Vps33 are absent, Sec17 inhibits fusion at an early stage. Thus, Vps33/HOPS promotes productive SNARE assembly in the presence of otherwise inhibitory Sec17. Once SNAREs are partially zipped, Sec17 promotes fusion in either the presence or absence of HOPS, but with faster kinetics when HOPS is absent, suggesting that ejection of the SM is a rate-limiting step.

中文翻译：

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Sec17 (α-SNAP) 和 SM 系绳复合物在体外和体内调节 SNARE 拉链的结果

跨越对接膜的 SNARE 复合物的拉链对于大多数细胞内融合事件是必不可少的。在这里，我们探讨了 SNARE 调节器如何在离散的拉链状态下运行。由 HOPS 及其 SM 亚基 Vps33 催化形成亚稳态反式复合物，随后是增加融合概率的拉链转变。Sec17 (α-SNAP) 独立于 Sec18 (NSF) 催化运行，抑制或刺激 SNARE 介导的融合。如果 HOPS 或 Vps33 不存在，Sec17 会在早期抑制融合。因此，Vps33/HOPS 在存在其他抑制性 Sec17 的情况下促进生产性 SNARE 组装。一旦 SNARE 被部分压缩，Sec17 在存在或不存在 HOPS 的情况下促进融合，但在不存在 HOPS 时具有更快的动力学，这表明 SM 的弹出是一个限速步骤。