Centre de Recherche du CHUQ, 2705 Boulevard Laurier, RC-9800 Québec, Canada G1V 4G2.
Biochem J. 2012 Dec 15;448(3):321-8. doi: 10.1042/BJ20121448.
The SAC (spindle assembly checkpoint) is a surveillance system that ensures the timely and accurate transmission of the genetic material to offspring. The process implies kinetochore targeting of the mitotic kinases Bub1 (budding uninhibited by benzamidine 1), BubR1 (Bub1 related) and Mps1 (monopolar spindle 1), which is mediated by the N-terminus of each kinase. In the present study we report the 1.8 Å (1 Å=0.1 nm) crystal structure of the TPR (tetratricopeptide repeat) domain in the N-terminal region of human Mps1. The structure reveals an overall high similarity to the TPR motif of the mitotic checkpoint kinases Bub1 and BubR1, and a number of unique features that include the absence of the binding site for the kinetochore structural component KNL1 (kinetochore-null 1; blinkin), and determinants of dimerization. Moreover, we show that a stretch of amino acids at the very N-terminus of Mps1 is required for dimer formation, and that interfering with dimerization results in mislocalization and misregulation of kinase activity. The results of the present study provide an important insight into the molecular details of the mitotic functions of Mps1 including features that dictate substrate selectivity and kinetochore docking.
纺锤体组装检验点（SAC）是一个监控系统，它可以确保遗传物质被准确无误地传递给后代。这个过程涉及到有丝分裂激酶 Bub1（苯甲脒抑制芽殖 1）、BubR1（Bub1 相关）和 Mps1（单极纺锤体 1）与着丝粒的靶向结合，这一过程由每个激酶的 N 端介导。在本研究中，我们报告了人源 Mps1 N 端区域 TPR（四肽重复）结构域的 1.8Å（1Å=0.1nm）晶体结构。该结构揭示了与有丝分裂检查点激酶 Bub1 和 BubR1 的 TPR 基序具有高度相似性，同时也存在一些独特的特征，包括缺乏与着丝粒结构成分 KNL1（kinetochore-null 1；blinkin）结合的位点，以及二聚体形成的决定因素。此外，我们还发现 Mps1 的 N 端非常起始处的一段氨基酸对于二聚体的形成是必需的，而干扰二聚体的形成会导致激酶活性的定位和调控异常。本研究的结果为 Mps1 的有丝分裂功能的分子细节提供了重要的见解，包括决定底物选择性和着丝粒对接的特征。
