Fbw7/hCDC4 dimerization regulates its substrate interactions
Markus Welcker1, Bruce E Clurman
1Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, Washington 98109, USA. mwelcker@fhcrc.org
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 F-box. 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.
Insights
Fbw7 ubiquitin ligase dimerization is essential for degrading oncogenes like cyclin E. However, additional phosphorylation can bypass this dimerization requirement, revealing a new regulatory mechanism for Fbw7 function.
Area of Science:
- Molecular Biology
- Biochemistry
- Cell Biology
Background:
- Fbw7 ubiquitin ligase targets key oncogenes (cyclin E, c-Myc, c-Jun, Notch) for degradation.
- Fission yeast Fbw7 homologs (pop1, pop2) are known to dimerize.
Purpose of the Study:
- To investigate if human Fbw7 dimerizes.
- To determine the functional impact of Fbw7 dimerization on oncogene degradation.
Main Methods:
- Investigated Fbw7 self-binding.
- Assessed the role of dimerization in Fbw7-cyclin E interaction.
- Analyzed the effect of phospho-degron modification on Fbw7 binding.
Main Results:
- Fbw7 efficiently binds to itself via a domain near its F-box.
- Fbw7 dimerization is crucial for stable interaction with the cyclin E T380 phospho-degron.
- Increased phosphorylation at S384 on the cyclin E phospho-degron can overcome the need for Fbw7 dimerization.
Conclusions:
- Fbw7-mediated cyclin E degradation is regulated by either Fbw7 dimerization or hyperphosphorylation of the T380 phospho-degron.
- Substrates lacking specific phospho-degron features may rely solely on Fbw7 dimerization for turnover.
- Identified a novel regulatory layer controlling Fbw7 substrate interaction and degradation.
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