title: A TPR domain-containing N-terminal module of MPS1 is required for its kinetochore localization by Aurora B.
abstract: The mitotic checkpoint ensures correct chromosome segregation by delaying cell cycle progression until all kinetochores have attached to the mitotic spindle. In this paper, we show that the mitotic checkpoint kinase MPS1 contains an N-terminal localization module, organized in an N-terminal extension (NTE) and a tetratricopeptide repeat (TPR) domain, for which we have determined the crystal structure. Although the module was necessary for kinetochore localization of MPS1 and essential for the mitotic checkpoint, the predominant kinetochore binding activity resided within the NTE. MPS1 localization further required HEC1 and Aurora B activity. We show that MPS1 localization to kinetochores depended on the calponin homology domain of HEC1 but not on Aurora B-dependent phosphorylation of the HEC1 tail. Rather, the TPR domain was the critical mediator of Aurora B control over MPS1 localization, as its deletion rendered MPS1 localization insensitive to Aurora B inhibition. These data are consistent with a model in which Aurora B activity relieves a TPR-dependent inhibitory constraint on MPS1 localization.
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands.
authors.forename: Wilco
authors.initials: W
authors.lastname: Nijenhuis
authors.forename: Eleonore
authors.initials: E
authors.lastname: von Castelmur
authors.forename: Dene
authors.initials: D
authors.lastname: Littler
authors.forename: Valeria
authors.initials: V
authors.lastname: De Marco
authors.forename: Eelco
authors.initials: E
authors.lastname: Tromer
authors.forename: Mathijs
authors.initials: M
authors.lastname: Vleugel
authors.forename: Maria H J
authors.initials: MH
authors.lastname: van Osch
authors.forename: Berend
authors.initials: B
authors.lastname: Snel
authors.forename: Anastassis
authors.initials: A
authors.lastname: Perrakis
authors.forename: Geert J P L
authors.initials: GJ
authors.lastname: Kops
mesh_terms: D000595:Amino Acid Sequence; D064107:Aurora Kinase B; D064127:Aurora Kinases; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism*; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins; D019143:Evolution, Molecular; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C120529:NDC80 protein, human; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human