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

eLife

Andrea Musacchio¹  Katharina Overlack²  Veronica Krenn²  Stefano Maffini²  Ivana Primorac²  Ingrid Hoffmann²  Geert J P L Kops³  Mathijs Vleugel⁴ 

[1] Department of Medical Oncology, University Medical Center Utrecht, Utrecht, Netherlands;Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany;Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands;Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands;

关键词: cell division;    centromere;    kinetochore;    spindle assembly checkpoint;    cell cycle;   

DOI  :  10.7554/eLife.05269

来源: DOAJ

【 摘 要 】

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. This 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. This 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.

【 授权许可】

Unknown