title: Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment.
abstract: 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.
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230026, China;
authors.forename: Zhen
authors.initials: Z
authors.lastname: Dou
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230026, China; Molecular Imaging Center, Morehouse School of Medicine, Atlanta, GA 30310;
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230026, China; Molecular Imaging Center, Morehouse School of Medicine, Atlanta, GA 30310;
authors.forename: Wenwen
authors.initials: W
authors.lastname: Wang
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230026, China; Molecular Imaging Center, Morehouse School of Medicine, Atlanta, GA 30310;
authors.forename: Tongge
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230026, China;
authors.forename: Xinghui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230026, China;
authors.forename: Leilei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, CNRS, University of Montpellier, 34090 Montpellier, France;
authors.forename: Ariane
authors.initials: A
authors.lastname: Abrieu
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230026, China; Department of Biochemistry, The University of Hong Kong, Hong Kong, China;
authors.forename: Chuanhai
authors.initials: C
authors.lastname: Fu
authors.affiliation: Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Hill
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Anhui Key Laboratory of Cellular Dynamics and Chemical Biology, University of Science and Technology of China, Hefei 230026, China; yaoxb@ustc.edu.cn.
authors.forename: Xuebiao
authors.initials: X
authors.lastname: Yao
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002875:Chromosomes / Q000648:ultrastructure; D015971:Gene Expression Regulation, Enzymologic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000378:metabolism* / Q000648:ultrastructure; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human
keywords: Mps1 kinase; chromosome alignment; kinetochore–microtubule attachment; reversine; spindle assembly checkpoint