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Molecular and Cellular Biology, August 2008, p. 4653-4664, Vol. 28, No. 15
0270-7306/08/$08.00+0     doi:10.1128/MCB.00055-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Pseudosubstrate Inhibition of the Anaphase-Promoting Complex by Acm1: Regulation by Proteolysis and Cdc28 Phosphorylation{triangledown}

Denis Ostapenko, Janet L. Burton, Ruiwen Wang, and Mark J. Solomon*

Yale University School of Medicine, Department of Molecular Biophysics and Biochemistry, 333 Cedar Street, New Haven, Connecticut 06520-8024

Received 11 January 2008/ Returned for modification 5 March 2008/ Accepted 22 May 2008

The ubiquitin ligase activity of the anaphase-promoting complex (APC)/cyclosome needs to be tightly regulated for proper cell cycle progression. Substrates are recruited to the APC by the Cdc20 and Cdh1 accessory proteins. The Cdh1-APC interaction is inhibited through phosphorylation of Cdh1 by Cdc28, the major cyclin-dependent protein kinase in budding yeast. More recently, Acm1 was reported to be a Cdh1-binding and -inhibitory protein in budding yeast. We found that although Acm1 is an unstable protein and contains the KEN-box and D-box motifs typically found in APC substrates, Acm1 itself is not an APC substrate. Rather, it uses these motifs to compete with substrates for Cdh1 binding, thereby inhibiting their recruitment to the APC. Mutation of these motifs prevented Acm1-Cdh1 binding in vivo and rendered Acm1 inactive both in vitro and in vivo. Acm1 stability was critically dependent on phosphorylation by Cdc28, as Acm1 was destabilized following inhibition of Cdc28, mutation of consensus Cdc28 phosphorylation sites in Acm1, or deletion of the Bmh1 and Bmh2 phosphoprotein-binding proteins. Thus, Cdc28 serves dual roles in inhibiting Cdh1-dependent APC activity during the cell cycle: stabilization of the Cdh1 inhibitor Acm1 and direct phosphorylation of Cdh1 to prevent its association with the APC.

* Corresponding author. Mailing address: Yale University School of Medicine, Department of Molecular Biophysics and Biochemistry, 333 Cedar Street, New Haven, CT 06520-8024. Phone: (203) 737-2702. Fax: (203) 785-6404. E-mail: Mark.Solomon{at}yale.edu

{triangledown} Published ahead of print on 2 June 2008.

Molecular and Cellular Biology, August 2008, p. 4653-4664, Vol. 28, No. 15
0270-7306/08/$08.00+0     doi:10.1128/MCB.00055-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Diamond, A. E., Park, J.-S., Inoue, I., Tachikawa, H., Neiman, A. M. (2009). The Anaphase Promoting Complex Targeting Subunit Ama1 Links Meiotic Exit to Cytokinesis during Sporulation in Saccharomyces cerevisiae. Mol. Biol. Cell 20: 134-145 [Abstract] [Full Text]  


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