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

ABSTRACT: 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 ultrase

SUBMITTER: Csizmok V 

PROVIDER: S-EPMC5216119 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature