Fbw7/hCDC4 dimerization regulates its substrate interactions
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BioMed Central
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Fbw7/hCDC4 dimerization regulates its substrate interactions Markus Welcker1 and Bruce E Clurman*1,2,3 Address: 1Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, Washington, 98109, USA, 2Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, Washington, 98109, USA and 3Department of Medicine, University of Washington School of Medicine, Seattle, Washington, 98104, USA Email: Markus Welcker - [email protected]; Bruce E Clurman* - [email protected] * Corresponding author
Published: 13 February 2007 Cell Division 2007, 2:7
doi:10.1186/1747-1028-2-7
Received: 29 November 2006 Accepted: 13 February 2007
This article is available from: http://www.celldiv.com/content/2/1/7 © 2007 Welcker and Clurman; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background: The Fbw7 ubiquitin ligase promotes the rapid degradation of several important oncogenes, such as cyclin E, c-Myc, c-Jun, and Notch. The two fission yeast homologs of Fbw7, pop1 and pop2, have previously been shown to dimerize. In this study, we asked whether Fbw7 can also dimerize and how dimerization affects Fbw7 function. Results: We found that Fbw7 binds efficiently to itself through a domain just upstream of its Fbox. We further show that dimerization is essential for the stable interaction of Fbw7 with the cyclin E T380 phospho-degron. Surprisingly, the requirement for dimerization can be suppressed by an additional phosphorylation of this phospho-degron at the +4 position (S384), which creates a binding site with higher affinity for monomeric Fbw7. Conclusion: Degradation of cyclin E by the Fbw7 pathway can, thus, be conditionally regulated either by Fbw7 dimerization or by hyperphosphorylation of the T380 phospho-degron. Other substrates, which cannot accommodate an extra phosphate in their phospho-degrons, or which don't provide a negatively charged amino acid in the +4 position, may be absolutely dependent on Fbw7 dimerization for their turnover. Our results point to an additional level of regulation for substrate interaction and turnover by Fbw7.
Background Fbw7 is the mammalian homolog of budding yeast CDC4 and mediates the degradation of several proteins involved in cell growth and division, including cyclin E, c-Myc, cJun, Notch, Presenilin, and SREBP [1-10]. Fbw7 recognizes a phospho-epitope, termed CPD (for Cdc4 Phospho-Degron), contained within these substrates. Via its Fbox, Fbw7 recruits the remainder of an SCF ubiquitin ligase complex, thus promoting substrate ubiquitination and rapid degradation by the proteasome [11]. Mammalian cells contain three Fbw7 isoforms (Fbw7α, Fbw7β, and Fbw7γ) that are produced by alternative splicing and
that localize to the
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