title: Aurora B phosphorylates spatially distinct targets to differentially regulate the kinetochore-microtubule interface.
abstract: Accurate chromosome segregation requires carefully regulated interactions between kinetochores and microtubules, but how plasticity is achieved to correct diverse attachment defects remains unclear. Here we demonstrate that Aurora B kinase phosphorylates three spatially distinct targets within the conserved outer kinetochore KNL1/Mis12 complex/Ndc80 complex (KMN) network, the key player in kinetochore-microtubule attachments. The combinatorial phosphorylation of the KMN network generates graded levels of microtubule-binding activity, with full phosphorylation severely compromising microtubule binding. Altering the phosphorylation state of each protein causes corresponding chromosome segregation defects. Importantly, the spatial distribution of these targets along the kinetochore axis leads to their differential phosphorylation in response to changes in tension and attachment state. In total, rather than generating exclusively binary changes in microtubule binding, our results suggest a mechanism for the tension-dependent fine-tuning of kinetochore-microtubule interactions.
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Julie P I
authors.initials: JP
authors.lastname: Welburn
authors.forename: Mathijs
authors.initials: M
authors.lastname: Vleugel
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lampson
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Fukagawa
authors.forename: Iain M
authors.initials: IM
authors.lastname: Cheeseman
mesh_terms: D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D015374:Biosensing Techniques; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002645:Chickens; D020090:Chromosome Segregation / Q000187:drug effects; D031541:Fluorescence Resonance Energy Transfer; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000187:drug effects / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D029742:Caenorhabditis elegans Proteins; C478660:KNL-1 protein, C elegans; C472643:Knl1 protein, human; C492664:MIS12 protein, human; D008869:Microtubule-Associated Proteins; C492665:NDC-80 protein, C elegans; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D050257:Tubulin Modulators; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases
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