Mps1 dimerization and multisite interactions with Ndc80 complex enable responsive spindle assembly checkpoint signaling
Mps1 dimerization and multisite interactions with Ndc80 complex enable responsive spindle assembly checkpoint signaling
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MPS1 二聚化和与 Ndc80 复合体的多位点相互作用可实现响应性主轴装配检查点信号传导
DOI：
10.1093/jmcb/mjaa006
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发表时间：
2020-07-01
影响因子：
5.5
通讯作者：
Dou, Zhen
中科院分区：
文献类型：
--
作者：
Gui, Ping;Sedzro, Divine M.;Dou, Zhen
无错误的有丝分裂依赖于染色体与纺锤体微管的精确连接，这是由纺锤体组装检查点（SAC）信号转导监测的。作为SAC的上游因子，Mps 1激酶的精确和动态的动粒定位对于启动和沉默SAC信号传导至关重要。然而，潜在的分子机制仍然难以捉摸。在这里，我们证明了Mps 1和Ndc 80复合物（Ndc 80 C）之间的多位点相互作用支配Mps 1动粒靶向。重要的是，我们确定了Mps 1 tetratricopeptide repeat domain和Ndc 80 C之间的直接相互作用。我们进一步确定了Mps 1的C-末端片段，其中包含蛋白激酶结构域和C-尾，增强Mps 1动粒定位。在机制上，Mps 1 C-末端片段介导其二聚化。C-尾的扰动减弱了Mps 1的动粒靶向和活性，导致由于SAC功能受损而导致的异常有丝分裂。总之，我们的研究强调了Mps 1二聚化和多位点相互作用与Ndc 80 C在实现响应SAC信号的重要性。
Error-free mitosis depends on accurate chromosome attachment to spindle microtubules, which is monitored by the spindle assembly checkpoint (SAC) signaling. As an upstream factor of SAC, the precise and dynamic kinetochore localization of Mps1 kinase is critical for initiating and silencing SAC signaling. However, the underlying molecular mechanism remains elusive. Here, we demonstrated that the multisite interactions between Mps1 and Ndc80 complex (Ndc80C) govern Mps1 kinetochore targeting. Importantly, we identified direct interaction between Mps1 tetratricopeptide repeat domain and Ndc80C. We further identified that Mps1 C-terminal fragment, which contains the protein kinase domain and C-tail, enhances Mps1 kinetochore localization. Mechanistically, Mps1 C-terminal fragment mediates its dimerization. Perturbation of C-tail attenuates the kinetochore targeting and activity of Mps1, leading to aberrant mitosis due to compromised SAC function. Taken together, our study highlights the importance of Mps1 dimerization and multisite interactions with Ndc80C in enabling responsive SAC signaling.