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

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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.

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Katharina Overlack

Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany

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The authors declare that no competing interests exist.
Ivana Primorac

Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany

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The authors declare that no competing interests exist.
Mathijs Vleugel

Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands Antilles

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The authors declare that no competing interests exist.
Veronica Krenn

Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany

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The authors declare that no competing interests exist.
Stefano Maffini

Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany

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The authors declare that no competing interests exist.
Ingrid Hoffmann

Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany

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The authors declare that no competing interests exist.
Geert J P L Kops

Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands

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The authors declare that no competing interests exist.
Andrea Musacchio

Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany

For correspondence
andrea.musacchio@mpi-dortmund.mpg.de

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The authors declare that no competing interests exist.

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