期刊
GENES & DEVELOPMENT
卷 27, 期 23, 页码 2531-2536出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.229195.113
关键词
Fbw7; SCF; phosphodegron; cyclin E
资金
- National Institutes of Health [CA084069, CA102742, CA107134, 2T32 GM007270]
- Howard Hughes Medical Institute
- Science Foundation Ireland [07/SK/B1242b, 10/IN.1/B2986]
- American Cancer Society
- Science Foundation Ireland (SFI) [07/SK/B1242b, 10/IN.1/B2986] Funding Source: Science Foundation Ireland (SFI)
The Fbw7 tumor suppressor targets a broad network of proteins for ubiquitylation. Here we show critical functions for Fbw7 dimerization in regulating the specificity and robustness of degradation. Dimerization enables Fbw7 to target substrates through concerted binding to two suboptimal and independent recognition sites. Accordingly, an endogenous dimerization-deficient Fbw7 mutation stabilizes suboptimal substrates. Dimerization increases Fbw7's robustness by preserving its function in the setting of mutations that disable Fbw7 monomers, thereby buffering against pathogenic mutations. Finally, dimerization regulates Fbw7 stability, and this likely involves Fbw7 trans-autoubiquitylation. Our study reveals novel functions of Fbw7 dimerization and an unanticipated complexity in substrate degradation.
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