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J. Biol. Chem., Vol. 280, Issue 34, 30301-30309, August 26, 2005

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Ubiquitination of p27^Kip1 Requires Physical Interaction with Cyclin E and Probable Phosphate Recognition by SKP2^*

Dana Ungermannova, Yuefeng Gao, and Xuedong Liu

From the Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309

p27^Kip1 is an essential cell cycle inhibitor of Cyclin-dependent kinases. Ubiquitin-mediated proteolysis of p27^Kip1 is an important mechanism for activation of Cyclin E-Cdk2 and facilitates G₁/S transition. Ubiquitination of p27 is primarily catalyzed by a multisubunit E3 ubiquitin ligase, SCF^Skp2, and requires an adapter protein Cks1. In addition, phosphorylation of p27 at Thr¹⁸⁷ by Cyclin E and Cdk2 is also essential for triggering substrate ubiquitination. Here we investigate the molecular mechanism of p27 ubiquitination. We show that Cyclin E-Cdk2 is essential for targeting the p27 substrate to SCF^Skp2. Direct physical contact between Cyclin E but not Cdk2 and p27 is required for p27 recruitment to SCF^Skp2. In a search for positively charged amino acid residues that may be involved in recognition of the Thr¹⁸⁷ phosphate group, we found that Arg³⁰⁶ of Skp2 is required for association and ubiquitination of phosphorylated p27 but dispensable for ubiquitination of unphosphorylated p21. Thus, our data unravel the molecular organization of the ubiquitination complex that catalyzes p27 ubiquitination and provide unique insights into the specificity of substrate recognition by SCF^Skp2.

Received for publication, September 28, 2004 , and in revised form, June 23, 2005.

^* This work was supported by National Institutes of Health CA107098-01 (to X. L.) The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Chemistry and Biochemistry, UCB 215, University of Colorado-Boulder, Boulder, CO 80309. Tel.: 303-735-6161; Fax: 303-735-6161; E-mail: Xuedong.Liu{at}colorado.edu.

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