Ubiquitylation of cyclin E requires the sequential function of SCF complexes containing distinct hCdc4 isoforms.
Cyclin E, an activator of cyclin-dependent kinase 2 (Cdk2), is targeted for proteasomal degradation by phosphorylation-dependent multiubiquitylation via the ubiquitin ligase SCF(hCdc4). SCF ubiquitin ligases are composed of a core of conserved subunits and one variable subunit (an F box protein) involved in substrate recognition. We show here that multiubiquitylation ... of cyclin E requires the sequential function of two distinct splice variant isoforms of the F box protein hCdc4 known as alpha and gamma. SCF(hCdc4alpha) binds a complex containing cyclin E, Cdk2, and the prolyl cis/trans isomerase Pin1 and promotes the activity of Pin1 without directly ubiquitylating cyclin E. However, due to the action of this SCF(hCdc4alpha)-Pin1 complex, cyclin E becomes an efficient ubiquitylation substrate of SCF(hCdc4gamma). Furthermore, in the context of Cdc4alpha and cyclin E, mutational data suggest that Pin1 isomerizes a noncanonical proline-proline bond, with the possibility that Cdc4alpha may serve as a cofactor for altering the specificity of Pin1.
Mesh Terms:
Binding Sites, Cell Cycle Proteins, Cell Line, Cyclin E, F-Box Proteins, Gene Silencing, Humans, Isoenzymes, Models, Biological, Mutation, Peptidylprolyl Isomerase, SKP Cullin F-Box Protein Ligases, Ubiquitin, Ubiquitin-Protein Ligases
Binding Sites, Cell Cycle Proteins, Cell Line, Cyclin E, F-Box Proteins, Gene Silencing, Humans, Isoenzymes, Models, Biological, Mutation, Peptidylprolyl Isomerase, SKP Cullin F-Box Protein Ligases, Ubiquitin, Ubiquitin-Protein Ligases
Mol. Cell
Date: Jul. 07, 2006
PubMed ID: 16818231
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