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Molecular and Cellular Biology, March 1999, p. 1759-1767, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Abundance of Cell Cycle Regulatory Protein Cdc4p Is Controlled by Interactions between Its F Box and Skp1p

Neal Mathias,1,* Steve Johnson,2,dagger Breck Byers,2 and Mark Goebl1

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Oncology Center, Indianapolis, Indiana 46202-5122,1 and Department of Genetics, University of Washington, Seattle, Washington 98195-73602

Received 10 August 1998/Returned for modification 21 September 1998/Accepted 5 December 1998

Posttranslational modification of a protein by ubiquitin usually results in rapid degradation of the ubiquitinated protein by the proteasome. The transfer of ubiquitin to substrate is a multistep process. Cdc4p is a component of a ubiquitin ligase that tethers the ubiquitin-conjugating enzyme Cdc34p to its substrates. Among the domains of Cdc4p that are crucial for function are the F-box, which links Cdc4p to Cdc53p through Skp1p, and the WD-40 repeats, which are required for binding the substrate for Cdc34p. In addition to Cdc4p, other F-box proteins, including Grr1p and Met30p, may similarly act together with Cdc53p and Skp1p to function as ubiquitin ligase complexes. Because the relative abundance of these complexes, known collectively as SCFs, is important for cell viability, we have sought evidence of mechanisms that modulate F-box protein regulation. Here we demonstrate that the abundance of Cdc4p is subject to control by a peptide segment that we term the R-motif (for "reduced abundance"). Furthermore, we show that binding of Skp1p to the F-box of Cdc4p inhibits R-motif-dependent degradation of Cdc4p. These results suggest a general model for control of SCF activities.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Dr., Indianapolis, IN 46202-5122. Phone: (317) 274-3743. Fax: (317) 274-4686. E-mail: neal{at}biochem4.iupui.edu.

dagger Present address: Genetics Department, Washington University, St. Louis, MO 63110.

Molecular and Cellular Biology, March 1999, p. 1759-1767, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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