Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms13943
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Funding
- Canadian Institutes of Health Research [MOP-57795, MOP-84281, MOP-126129, MOP-114985]
- Canadian Cancer Society Research Institute [703906, 703477]
- Ministere de l'enseignement superieur, de la recherche, de la science et de la technologie du Quebec through Genome Quebec
- Canada Research Chair in Structural Biology
- Canada Research Chair in Systems and Synthetic Biology
- Canada Research Chair in Intrinsically Disordered Proteins
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The ubiquitin ligase SCFCdc4 mediates phosphorylation-dependent elimination of numerous substrates by binding one or more Cdc4 phosphodegrons (CPDs). Methyl-based NMR analysis of the Cdc4 WD40 domain demonstrates that Cyclin E, Sic1 and Ash1 degrons have variable effects on the primary Cdc4(WD40) binding pocket. Unexpectedly, a Sic1-derived multi-CPD substrate (pSic1)perturbs methyls around a previously documented allosteric binding site for the chemical inhibitor SCF-I2. NMR cross-saturation experiments confirm direct contact between pSic1 and the allosteric pocket. Phosphopeptide affinity measurements reveal negative allosteric communication between the primary CPD and allosteric pockets. Mathematical modelling indicates that the allosteric pocket may enhance ultra-sensitivity by tethering pSic1 to Cdc4. These results suggest negative allosteric interaction between two distinct binding pockets on the Cdc4(WD40) domain may facilitate dynamic exchange of multiple CPD sites to confer ultrasensitive dependence on substrate phosphorylation.
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