A molecular basis for the differential roles of Bub1 and BubR1 in the spindle assembly checkpoint

  1. Katharina Overlack
  2. Ivana Primorac
  3. Mathijs Vleugel
  4. Veronica Krenn
  5. Stefano Maffini
  6. Ingrid Hoffmann
  7. Geert J P L Kops
  8. Andrea Musacchio  Is a corresponding author
  1. Max Planck Institute of Molecular Physiology, Germany
  2. University Medical Center Utrecht, Netherlands Antilles
  3. University Medical Center Utrecht, Netherlands

Abstract

The spindle assembly checkpoint (SAC) monitors and promotes kinetochore-microtubule attachment during mitosis. Bub1 and BubR1, SAC components, originated from duplication of an ancestor gene. Subsequent sub-functionalization established subordination: Bub1, recruited first to kinetochores, promotes successive BubR1 recruitment. Because both Bub1 and BubR1 hetero-dimerize with Bub3, a targeting adaptor for phosphorylated kinetochores, the molecular basis for such sub-functionalization is unclear. We demonstrate that Bub1, but not BubR1, enhances binding of Bub3 to phosphorylated kinetochores. Grafting a short motif of Bub1 onto BubR1 promotes Bub1-independent kinetochore recruitment of BubR1. Such gain-of-function BubR1 mutant cannot sustain a functional checkpoint. We demonstrate that kinetochore localization of BubR1 relies on direct hetero-dimerization with Bub1 at a pseudo-symmetric interface. Such pseudo-symmetric interaction underpins a template-copy relationship crucial for kinetochore-microtubule attachment and SAC signaling. Our results illustrate how gene duplication and sub-functionalization shape the workings of an essential molecular network.

Article and author information

Author details

  1. Katharina Overlack

    Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Ivana Primorac

    Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Mathijs Vleugel

    Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands Antilles
    Competing interests
    The authors declare that no competing interests exist.
  4. Veronica Krenn

    Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Stefano Maffini

    Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Ingrid Hoffmann

    Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Geert J P L Kops

    Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Andrea Musacchio

    Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    For correspondence
    andrea.musacchio@mpi-dortmund.mpg.de
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Stephen C Harrison, Howard Hughes Medical Institute, Harvard Medical School, United States

Version history

  1. Received: October 21, 2014
  2. Accepted: January 21, 2015
  3. Accepted Manuscript published: January 22, 2015 (version 1)
  4. Version of Record published: February 18, 2015 (version 2)

Copyright

© 2015, Overlack et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Katharina Overlack
  2. Ivana Primorac
  3. Mathijs Vleugel
  4. Veronica Krenn
  5. Stefano Maffini
  6. Ingrid Hoffmann
  7. Geert J P L Kops
  8. Andrea Musacchio
(2015)
A molecular basis for the differential roles of Bub1 and BubR1 in the spindle assembly checkpoint
eLife 4:e05269.
https://doi.org/10.7554/eLife.05269

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https://doi.org/10.7554/eLife.05269

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