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Vol. 11, Issue 5, 1597-1609, May 2000

Activating Phosphorylation of the Saccharomyces cerevisiae Cyclin-dependent Kinase, Cdc28p, Precedes Cyclin Binding

Karen E. Ross,* Philipp Kaldis,dagger Dagger and Mark J. Solomondagger Dagger

Departments of  *Cell Biology and  dagger Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520-2114

Eukaryotic cell cycle progression is controlled by a family of protein kinases known as cyclin-dependent kinases (Cdks). Two steps are essential for Cdk activation: binding of a cyclin and phosphorylation on a conserved threonine residue by the Cdk-activating kinase (CAK). We have studied the interplay between these regulatory mechanisms during the activation of the major Saccharomyces cerevisiae Cdk, Cdc28p. We found that the majority of Cdc28p was phosphorylated on its activating threonine (Thr-169) throughout the cell cycle. The extent of Thr-169 phosphorylation was similar for monomeric Cdc28p and Cdc28p bound to cyclin. By varying the order of the addition of cyclin and Cak1p, we determined that Cdc28p was activated most efficiently when it was phosphorylated before cyclin binding. Furthermore, we found that a Cdc28pT169A mutant, which cannot be phosphorylated, bound cyclin less well than wild-type Cdc28p in vivo. These results suggest that unphosphorylated Cdc28p may be unable to bind tightly to cyclin. We propose that Cdc28p is normally phosphorylated by Cak1p before it binds cyclin. This activation pathway contrasts with that in higher eukaryotes, in which cyclin binding appears to precede activating phosphorylation.

Dagger Corresponding authors. E-mail addresses: mark.solomon{at}yale.edu, solomon.lab{at}yale.edu.

Molecular Biology of the Cell
Vol. 11, 1597-1609, May 2000
Copyright © 2000 by The American Society for Cell Biology


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