Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases.

The ubiquitin-mediated proteolysis of cyclin E plays a central role in cell-cycle progression, and cyclin E accumulation is a common event in cancer. Cyclin E degradation is triggered by multisite phosphorylation, which induces binding to the SCF(Fbw7) ubiquitin ligase complex. Structures of the Skp1-Fbw7 complex bound to cyclin E peptides ...
identify a doubly phosphorylated pThr380/pSer384 cyclin E motif as an optimal, high-affinity degron and a singly phosphorylated pThr62 motif as a low-affinity one. Biochemical data indicate that the closely related yeast SCF(Cdc4) complex recognizes the multisite phosphorylated Sic1 substrate similarly and identify three doubly phosphorylated Sic1 degrons, each capable of high-affinity interactions with two Cdc4 phosphate binding sites. A model that explains the role of multiple cyclin E/Sic1 degrons is provided by the findings that Fbw7 and Cdc4 dimerize, that Fbw7 dimerization enhances the turnover of a weakly associated cyclin E in vivo, and that Cdc4 dimerization increases the rate and processivity of Sic1 ubiquitination in vitro.
Mesh Terms:
Amino Acid Sequence, Binding Sites, Cell Cycle Proteins, Cell Line, Cyclin E, Cyclin-Dependent Kinase Inhibitor Proteins, Dimerization, F-Box Proteins, Humans, Models, Biological, Molecular Sequence Data, Phosphopeptides, Phosphorylation, Protein Binding, Protein Structure, Tertiary, S-Phase Kinase-Associated Proteins, SKP Cullin F-Box Protein Ligases, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Serine, Structure-Activity Relationship, Substrate Specificity, Threonine, Transfection, Ubiquitin, Ubiquitin-Protein Ligases
Mol. Cell
Date: Apr. 13, 2007
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