Pseudosubstrate Inhibition of APCCdh1 by Acm1: Regulation by Proteolysis and Cdc28 Phosphorylation.

@article{citeulike:2881847, abstract = {The ubiquitin ligase activity of the anaphase-promoting complex/cyclosome (APC/C) 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 APC(Cdh1) activity during the cell cycle: stabilization of the Cdh1 inhibitor Acm1 and direct phosphorylation of Cdh1 to prevent its association with the APC.}, address = {Yale University School of Medicine, Department of Molecular Biophysics and Biochemistry, 333 Cedar Street, New Haven, CT 06520-8024.}, author = {Ostapenko, Denis and Burton, Janet L L. and Wang, Ruiwen and Solomon, Mark J J. }, citeulike-article-id = {2881847}, doi = {http://dx.doi.org/10.1128/MCB.00055-08}, issn = {1098-5549}, journal = {Molecular and cellular biology}, keywords = {apc, cell, cycle, dbox, kenbox, ubiquitin}, month = {June}, posted-at = {2008-06-11 08:53:15}, priority = {2}, title = {Pseudosubstrate Inhibition of APCCdh1 by Acm1: Regulation by Proteolysis and Cdc28 Phosphorylation.}, url = {http://dx.doi.org/10.1128/MCB.00055-08}, year = {2008} }

TY - JOUR ID - citeulike:2881847 L3 - citeulike-article-id:2881847 TI - Pseudosubstrate Inhibition of APCCdh1 by Acm1: Regulation by Proteolysis and Cdc28 Phosphorylation. JF - Molecular and cellular biology AD - Yale University School of Medicine, Department of Molecular Biophysics and Biochemistry, 333 Cedar Street, New Haven, CT 06520-8024. SN - 1098-5549 N2 - The ubiquitin ligase activity of the anaphase-promoting complex/cyclosome (APC/C) 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 APC(Cdh1) activity during the cell cycle: stabilization of the Cdh1 inhibitor Acm1 and direct phosphorylation of Cdh1 to prevent its association with the APC. KW - apc KW - cell KW - cycle KW - dbox KW - kenbox KW - ubiquitin AU - Ostapenko, Denis AU - Burton, Janet L AU - Wang, Ruiwen AU - Solomon, Mark J PY - 2008/06/02/ UR - http://dx.doi.org/10.1128/MCB.00055-08 ER -