Catalytic assembly of the mitotic checkpoint inhibitor BubR1-Cdc20 by a Mad2-induced functional Switch in Cdc20

Joo Seok Han, Andrew J. Holland, Daniele Fachinetti, Anita Kulukian, Bulent Cetin, Don W. Cleveland

Research output: Contribution to journalArticle

Abstract

The mitotic checkpoint acts to maintain chromosome content by generation of a diffusible anaphaseinhibitor. Unattached kinetochores catalyze a conformational shift in Mad2, converting an inactive open form into a closed form that can capture Cdc20, the mitotic activator of the APC/C ubiquitin ligase. Mad2 binding is now shown to promote a functional switch in Cdc20, exposing a previously inaccessible site for binding to BubR1's conserved Mad3 homology domain. BubR1, but not Mad2, binding to APC/CCdc20 is demonstrated to inhibit ubiquitination of cyclin B. Closed Mad2 is further shown to catalytically amplify production of BubR1-Cdc20 without necessarily being part of the complex. Thus, the mitotic checkpoint is produced by a cascade of two catalytic steps: an initial step acting at unattached kinetochores to produce a diffusible Mad2-Cdc20 intermediate and a diffusible step in which that intermediate amplifies production of BubR1-Cdc20, the inhibitor of cyclin B ubiquitination, by APC/CCdc20.

Original languageEnglish (US)
Pages (from-to)92-104
Number of pages13
JournalMolecular cell
Volume51
Issue number1
DOIs
StatePublished - Jul 11 2013

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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