Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 33; pp. E4546 - E4555
• Main Authors: Dou, Zhen, Liu, Xing, Wang, Wenwen, Zhu, Tongge, Wang, Xinghui, Xu, Leilei, Abrieu, Ariane, Fu, Chuanhai, Hill, Donald L., Yao, Xuebiao
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.08.2015; National Acad Sciences
• Series: PNAS Plus
• Subjects: Amino Acid Sequence; Biochemistry, Molecular Biology; Biological Sciences; Biophysics; Cell Cycle Proteins - metabolism; Cell division; Cellular Biology; Chromosomes; Chromosomes - ultrastructure; Gene Expression Regulation, Enzymologic; Green Fluorescent Proteins - metabolism; HeLa Cells; Humans; Kinases; Kinetochores - metabolism; Kinetochores - ultrastructure; Life Sciences; Microtubules - metabolism; Mitosis; Molecular Sequence Data; PNAS Plus; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Sequence Homology, Amino Acid; reversine; Mps1 kinase; kinetochore–microtubule attachment; chromosome alignment; spindle assembly checkpoint
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1508791112

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.