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Mol Cell. 2009 Apr 10;34(1):68-80. doi: 10.1016/j.molcel.2009.02.027.

Analysis of activator-binding sites on the APC/C supports a cooperative substrate-binding mechanism.

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1
Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA.

Abstract

The anaphase-promoting complex or cyclosome (APC/C) is a ubiquitin ligase essential for the completion of mitosis in all eukaryotic cells. Substrates are recruited to the APC/C by activator proteins (Cdc20 or Cdh1), but it is not known where substrates are bound during catalysis. We explored this problem by analyzing mutations in the tetratricopeptide-repeat-containing APC/C subunits. We identified residues in Cdc23 and Cdc27 that are required for APC/C binding to Cdc20 and Cdh1 and for APC/C function in vivo. Mutation of these sites increased the rate of activator dissociation from the APC/C but did not affect reaction processivity, suggesting that the mutations have little effect on substrate dissociation from the active site. Further studies revealed that activator dissociation from the APC/C is inhibited by substrate, and that substrates are not bound solely to activator during catalysis but interact bivalently with an additional binding site on the APC/C core.

PMID:
19362536
PMCID:
PMC2754851
DOI:
10.1016/j.molcel.2009.02.027
[Indexed for MEDLINE]
Free PMC Article
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