Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment
Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment
复制标题
Mps1 激酶动态定位至动粒对于纺锤体微管的精确附着至关重要
DOI：
10.1073/pnas.1508791112
复制
发表时间：
2015-08-18
影响因子：
11.1
通讯作者：
Yao, Xuebiao
中科院分区：
文献类型：
--
作者：
Dou, Zhen;Liu, Xing;Yao, Xuebiao
意义 纺锤体装配检查点 (SAC) 作为一种监视机制，确保细胞分裂过程中遗传物质的准确分离。蛋白激酶单极纺锤体 1 (Mps1) 在 SAC 中发挥着关键作用，但 Mps1 在染色体分离中的作用机制仍不清楚。在这项研究中，我们确定了一个先前未定义的 Mps1 结构决定因素，名为“IRK”（着丝粒定位的内部区域），并证明了其在准确的着丝粒-微管附着中的功能重要性。从机制上讲，Mps1 和核分裂周期 80 复合体 (Ndc80C) 之间的动态分层相互作用协调精确的有丝分裂，因为非活性 Mps1 与 Ndc80C 通过 IRK 的持续关联会扰乱正确的动粒-微管附着。我们的结果为有丝分裂中动粒处 Mps1 活性的时空动力学提供了新的机制见解。纺锤体组装检查点 (SAC) 是一种保守的信号通路，可监测有丝分裂过程中染色体的忠实分离。作为 SAC 的核心组成部分，进化上保守的激酶单极纺锤体 1 (Mps1) 与调节染色体排列有关，但其潜在的分子机制仍不清楚。我们对 SAC 中 Mps1 活性的分子描述发现了一个先前未识别的结构决定因素，它是 Mps1 在动粒功能的基础。在这里，我们表明 Mps1 包含一个与四肽重复结构域相邻的着丝点定位 (IRK) 内部区域。重要的是，IRK 区域决定失活 Mps1 的动粒定位，失活 Mps1 的积累会扰乱准确的染色体排列和有丝分裂进展。从机制上讲，IRK 区域与核分裂周期 80 复合体 (Ndc80C) 结合，并且失活的 Mps1 在着丝粒处的积累阻止了 Ndc80C 和纺锤体微管 (MT) 之间的动态相互作用，从而导致异常的着丝粒附着。因此，我们的结果提出了一种以前未定义的机制，Mps1 通过协调 Ndc80C-MT 相互作用在染色体排列中发挥作用，并强调了 Mps1 激酶活性和动粒定位的精确时空调节在准确有丝分裂进展中的重要性。
Significance The spindle assembly checkpoint (SAC) works as a surveillance mechanism to ensure accurate segregation of genetic materials during cell division. Protein kinase monopolar spindle 1 (Mps1) plays a key role in SAC, but the mechanism of Mps1 action in chromosome segregation remains elusive. In this study, we identified a previously undefined structural determinant of Mps1 named “IRK” (internal region for kinetochore localization) and demonstrated its functional importance in accurate kinetochore–microtubule attachment. Mechanistically, a dynamic hierarchical interaction between Mps1 and the nuclear division cycle 80 complex (Ndc80C) orchestrates accurate mitosis, because persistent association of inactive Mps1 with Ndc80C via the IRK perturbs correct kinetochore–microtubule attachment. Our results provide a new mechanistic insight into the spatiotemporal dynamics of Mps1 activity at the kinetochore in mitosis. The spindle assembly checkpoint (SAC) is a conserved signaling pathway that monitors faithful chromosome segregation during mitosis. As a core component of SAC, the evolutionarily conserved kinase monopolar spindle 1 (Mps1) has been implicated in regulating chromosome alignment, but the underlying molecular mechanism remains unclear. Our molecular delineation of Mps1 activity in SAC led to discovery of a previously unidentified structural determinant underlying Mps1 function at the kinetochores. Here, we show that Mps1 contains an internal region for kinetochore localization (IRK) adjacent to the tetratricopeptide repeat domain. Importantly, the IRK region determines the kinetochore localization of inactive Mps1, and an accumulation of inactive Mps1 perturbs accurate chromosome alignment and mitotic progression. Mechanistically, the IRK region binds to the nuclear division cycle 80 complex (Ndc80C), and accumulation of inactive Mps1 at the kinetochores prevents a dynamic interaction between Ndc80C and spindle microtubules (MTs), resulting in an aberrant kinetochore attachment. Thus, our results present a previously undefined mechanism by which Mps1 functions in chromosome alignment by orchestrating Ndc80C–MT interactions and highlight the importance of the precise spatiotemporal regulation of Mps1 kinase activity and kinetochore localization in accurate mitotic progression.