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

Katharina Overlack, Ivana Primorac, Mathijs Vleugel, Veronica Krenn, Stefano Maffini, Ingrid Hoffmann, Geert J P L Kops, Andrea Musacchio

Research output: Contribution to journalArticlepeer-review


The spindle assembly checkpoint (SAC) monitors and promotes kinetochoremicrotubule attachment during mitosis. Bubl and BubRl, SAC components, originated from duplication of an ancestor gene. Subsequent subfunctionalization established subordination: Bubl, recruited first to kinetochores, promotes successive BubRl recruitment. Because both Bubl and BubRl hetero- dimerize with Bub3, a targeting adaptor for phosphorylated kinetochores, the molecular basis for such sub-functionalization is unclear. We demonstrate that Bubl, but not BubRl, enhances binding of Bub3 to phosphorylated kinetochores. Grafting a short motif of Bubl onto BubRl promotes Bubl-independent kinetochore recruitment of BubRl. Such gain-of-function BubRl mutant cannot sustain a functional checkpoint. We demonstrate that kinetochore localization of BubRl relies on direct hetero-dimerization with Bubl 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.

Original languageEnglish
Article numbere05269
Issue number4
Publication statusPublished - Jan 22 2015


  • Bub1
  • Bub3
  • BubR1
  • Casc5
  • Cdc20
  • Cell cycle
  • Divergence
  • Escape from adaptive conflict
  • Evolution
  • Gene duplication
  • Kinetochore
  • KMN network
  • Knl1
  • Mad2
  • Mis12
  • Mitotic checkpoint
  • Mps1
  • Reversine
  • Spindle assembly checkpoint
  • Sub-functionalization

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)


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