An APC/C inhibitor stabilizes cyclin B1 by prematurely terminating ubiquitination

Xing Zeng, Randall W. King

Research output: Contribution to journalArticlepeer-review

Abstract

The anaphase-promoting complex/cyclosome (APC) is a ubiquitin ligase that is required for exit from mitosis. We previously showed that tosyl arginine methyl ester (TAME) inhibits APC-dependent proteolysis by competing with the C-terminal isoleucine-arginine tail of the APC activator cell division cycle 20 (Cdc20) for APC binding. Here we show that in the absence of APC substrates, TAME ejects Cdc20 from the APC by promoting Cdc20 autoubiquitination in its N-terminal region. Cyclin B1 antagonizes TAME's effect by promoting binding of free Cdc20 to the APC and by suppressing Cdc20 autoubiquitination. Nevertheless, TAME stabilizes cyclin B1 in Xenopus extracts by two mechanisms. First, it reduces the kcat of the APC-Cdc20-cyclin B1 complex without affecting the Km, slowing the initial ubiquitination of unmodified cyclin B1. Second, as cyclin B1 becomes ubiquitinated, it loses its ability to promote Cdc20 binding to the APC in the presence of TAME. As a result, cyclin B1 ubiquitination terminates before reaching the threshold necessary for proteolysis.

Original languageEnglish (US)
Pages (from-to)383-392
Number of pages10
JournalNature chemical biology
Volume8
Issue number4
DOIs
StatePublished - Apr 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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