Structure of a Fbw7-Skp1-Cyclin E Complex: Multisite-Phosphorylated Substrate Recognition by SCF Ubiquitin Ligases Journal Article
| Authors: | Hao, B.; Oehlmann, S.; Sowa, M. E.; Harper, J. W.; Pavletich, N. P. |
| Article Title: | Structure of a Fbw7-Skp1-Cyclin E Complex: Multisite-Phosphorylated Substrate Recognition by SCF Ubiquitin Ligases |
| Abstract: | 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 SCFFbw7 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 SCFCdc4 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. © 2007 Elsevier Inc. All rights reserved. |
| Keywords: | controlled study; protein phosphorylation; unclassified drug; human cell; ubiquitin; protein domain; protein motif; cell cycle proteins; complex formation; models, biological; serine; ubiquitin protein ligase; cell line; protein; protein binding; enzyme substrate; transfection; structure-activity relationship; phosphorylation; ubiquitination; amino acid sequence; molecular sequence data; sequence homology, amino acid; hybrid protein; saccharomyces cerevisiae; substrate specificity; binding site; cellcycle; dimerization; protein structure, tertiary; threonine; binding sites; saccharomyces cerevisiae proteins; protein structure; ubiquitin-protein ligases; cyclin e; s-phase kinase-associated proteins; skp cullin f-box protein ligases; f-box proteins; phosphopeptides; f box protein; protein fbw7; protein sic1; s phase kinase associated protein; s phase kinase associated protein 1 |
| Journal Title: | Molecular Cell |
| Volume: | 26 |
| Issue: | 1 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2007-04-13 |
| Start Page: | 131 |
| End Page: | 143 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2007.02.022 |
| PUBMED: | 17434132 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 84" - "Export Date: 17 November 2011" - "CODEN: MOCEF" - "Source: Scopus" |
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