SKP1 CONNECTS CELL-CYCLE REGULATORS TO THE UBIQUITIN PROTEOLYSIS MACHINERY THROUGH A NOVEL MOTIF, THE F-BOX

We have identified the yeast and human homologs of the SKP1 gene as a suppressor of cdc4 mutants and as a cyclin F-binding protein. Skp1p in directly binds cyclin A/Cdk2 through Skp2p, and directly binds Skp2p, cyclin F, and Cdc4p through a novel structural motif called the F-box. SKP1 is required for ubiquitin-mediated proteolysis of Cln2p, Clb5p, and the Cdk inhibitor Sic1p, and provides a link between these molecul es and the proteolysis machinery. A large number of proteins contain t he F-box motif and are thereby implicated in the ubiquitin pathway. Di fferent skp1 mutants arrest cells in either G1 or G2, suggesting a con nection between regulation of proteolysis in different stages of the c ycle.