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An allosteric conduit facilitates dynamic multisite substrate recognition by the SCF(Cdc4) ubiquitin ligase.

Csizmok V, Orlicky S, Cheng J, Song J, Bah A, Delgoshaie N, Lin H, Mittag T, Sicheri F, Chan HS, Tyers M, Forman-Kay JD

Molecular Structure &Function, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.

The ubiquitin ligase SCF(Cdc4) 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 ultrasensitivity 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.

Nat Commun 2017;8:13943.

Pubmed ID: 28045046

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