title: Structure of the MIS12 Complex and Molecular Basis of Its Interaction with CENP-C at Human Kinetochores.
abstract: Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. MIS12C, on the other hand, connects the KMN to the chromosome-proximal domain of the kinetochore through a direct interaction with CENP-C. The structural basis for this crucial bridging function of MIS12C is unknown. Here, we report crystal structures of human MIS12C associated with a fragment of CENP-C and unveil the role of Aurora B kinase in the regulation of this interaction. The structure of MIS12:CENP-C complements previously determined high-resolution structures of functional regions of NDC80C and KNL1C and allows us to build a near-complete structural model of the KMN assembly. Our work illuminates the structural organization of essential chromosome segregation machinery that is conserved in most eukaryotes.
authors.affiliation: Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany. Electronic address: arsen.petrovic@mpi-dortmund.mpg.de.
authors.forename: Arsen
authors.initials: A
authors.lastname: Petrovic
authors.affiliation: Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Keller
authors.affiliation: Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Overlack
authors.affiliation: Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: John
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115.
authors.forename: Yoana N
authors.initials: YN
authors.lastname: Dimitrova
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115.
authors.forename: Simon
authors.initials: S
authors.lastname: Jenni
authors.affiliation: Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
authors.forename: Suzan
authors.initials: S
authors.lastname: van Gerwen
authors.affiliation: Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Stege
authors.affiliation: Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Wohlgemuth
authors.affiliation: Gene Center Munich, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 25, 81377 Munich, Germany.
authors.forename: Pascaline
authors.initials: P
authors.lastname: Rombaut
authors.affiliation: Gene Center Munich, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 25, 81377 Munich, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Herzog
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115; Department of Biological Chemistry and Molecular Pharmacology, Howard Hughes Medical Institute, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harrison
authors.affiliation: Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany. Electronic address: ingrid.vetter@mpi-dortmund.mpg.de.
authors.forename: Ingrid R
authors.initials: IR
authors.lastname: Vetter
authors.affiliation: Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany; Faculty of Biology, Centre for Medical Biotechnology, University Duisburg-Essen, Universitätsstrasse, 45141 Essen, Germany. Electronic address: andrea.musacchio@mpi-dortmund.mpg.de.
authors.forename: Andrea
authors.initials: A
authors.lastname: Musacchio
mesh_terms: D000818:Animals; D064107:Aurora Kinase B / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins; D006801:Humans; D018386:Kinetochores / Q000737:chemistry*; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D003598:Cytoskeletal Proteins; C532764:DSN1 protein, human; C472643:Knl1 protein, human; C492664:MIS12 protein, human; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; C120529:NDC80 protein, human; D009687:Nuclear Proteins; C060905:centromere protein C; C576921:AURKB protein, human; D064107:Aurora Kinase B
keywords: CCAN; CENP-C; DSN1; KMN network; MIND; Mis12; NSL1; PMF1; centromere; kinetochore