title: The kinetochore encodes a mechanical switch to disrupt spindle assembly checkpoint signalling.
abstract: The spindle assembly checkpoint (SAC) is a unique signalling mechanism that responds to the state of attachment of the kinetochore to spindle microtubules. SAC signalling is activated by unattached kinetochores, and it is silenced after these kinetochores form end-on microtubule attachments. Although the biochemical cascade of SAC signalling is well understood, how kinetochore-microtubule attachment disrupts it remained unknown. Here we show that, in budding yeast, end-on microtubule attachment to the kinetochore physically separates the Mps1 kinase, which probably binds to the calponin homology domain of Ndc80, from the kinetochore substrate of Mps1, Spc105 (KNL1 orthologue). This attachment-mediated separation disrupts the phosphorylation of Spc105, and enables SAC silencing. Additionally, the Dam1 complex may act as a barrier that shields Spc105 from Mps1. Together these data suggest that the protein architecture of the kinetochore encodes a mechanical switch. End-on microtubule attachment to the kinetochore turns this switch off to silence the SAC.
authors.affiliation: Biophysics, University of Michigan, 930 N. University Avenue Ann Arbor, Michigan 48109, USA.
authors.forename: Pavithra
authors.initials: P
authors.lastname: Aravamudhan
authors.affiliation: Cell and developmental biology, University of Michigan, 109 Zina Pitcher Place, 3067 BSRB Ann Arbor, Michigan 48109, USA.
authors.forename: Alan A
authors.initials: AA
authors.lastname: Goldfarb
authors.affiliation: 1] Biophysics, University of Michigan, 930 N. University Avenue Ann Arbor, Michigan 48109, USA [2] Cell and developmental biology, University of Michigan, 109 Zina Pitcher Place, 3067 BSRB Ann Arbor, Michigan 48109, USA.
authors.forename: Ajit P
authors.initials: AP
authors.lastname: Joglekar
mesh_terms: D064127:Aurora Kinases / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D018386:Kinetochores / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D015739:Nocodazole / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D008941:Spindle Apparatus / Q000378:metabolism*; D059008:Time-Lapse Imaging / Q000379:methods; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; C116003:DAM1 protein, S cerevisiae; D008164:Luminescent Proteins; C501382:MAD1 protein, S cerevisiae; D008869:Microtubule-Associated Proteins; C112472:NDC80 protein, S cerevisiae; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; C546124:Spc105 protein, S cerevisiae; D050257:Tubulin Modulators; D064127:Aurora Kinases; C576961:IPL1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C093416:MPS1 protein, S cerevisiae; D015739:Nocodazole; D020123:Sirolimus