Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment.
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.
['Dou|Zhen|Z|', 'Liu|Xing|X|', 'Wang|Wenwen|W|', 'Zhu|Tongge|T|', 'Wang|Xinghui|X|', 'Xu|Leilei|L|', 'Abrieu|Ariane|A|', 'Fu|Chuanhai|C|', 'Hill|Donald L|DL|', 'Yao|Xuebiao|X|']
D000595:Amino Acid Sequence D018797:Cell Cycle Proteins D002875:Chromosomes D015971:Gene Expression Regulation, Enzymologic D049452:Green Fluorescent Proteins D006367:HeLa Cells D006801:Humans D018386:Kinetochores D008870:Microtubules D008938:Mitosis D008969:Molecular Sequence Data D017346:Protein Serine-Threonine Kinases D017434:Protein Structure, Tertiary D011505:Protein-Tyrosine Kinases D034622:RNA Interference D034741:RNA, Small Interfering D017386:Sequence Homology, Amino Acid
Mps1 kinase spindle assembly checkpoint chromosome alignment kinetochore–microtubule attachment reversine