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

Molecular cell | Apr 13, 2007

http://www.ncbi.nlm.nih.gov/pubmed/17434132

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.

Pubmed ID: 17434132 RIS Download

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

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Associated grants

  • Agency: NIA NIH HHS, Id: R01 AG011085

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