Cand1-Mediated Adaptive Exchange Mechanism Enables Variation in F-Box Protein Expression

• Published in: Molecular cell Vol. 69; no. 5; pp. 773 - 786.e6
• Main Authors: Liu, Xing, Reitsma, Justin M., Mamrosh, Jennifer L., Zhang, Yaru, Straube, Ronny, Deshaies, Raymond J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2018
• Subjects: Animals; Cand1; Cullin Proteins - chemistry; Cullin Proteins - genetics; Cullin Proteins - metabolism; exchange factor; F-Box Proteins - biosynthesis; F-Box Proteins - chemistry; F-Box Proteins - genetics; Gene Expression Regulation; mathematical modeling; Mice; Models, Biological; Models, Chemical; NEDD8 Protein - chemistry; NEDD8 Protein - genetics; NEDD8 Protein - metabolism; Proteolysis; SCF cycle; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; ubiquitin ligase; Cand1; ubiquitin ligase; mathematical modeling; exchange factor; SCF cycle
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.01.038

Skp1⋅Cul1⋅F-box (SCF) ubiquitin ligase assembly is regulated by the interplay of substrate binding, reversible Nedd8 conjugation on Cul1, and the F-box protein (FBP) exchange factors Cand1 and Cand2. Detailed investigations into SCF assembly and function in reconstituted systems and Cand1/2 knockout cells informed the development of a mathematical model for how dynamical assembly of SCF complexes is controlled and how this cycle is coupled to degradation of an SCF substrate. Simulations predicted an unanticipated hypersensitivity of Cand1/2-deficient cells to FBP expression levels, which was experimentally validated. Together, these and prior observations lead us to propose the adaptive exchange hypothesis, which posits that regulation of the koff of an FBP from SCF by the actions of substrate, Nedd8, and Cand1 molds the cellular repertoire of SCF complexes and that the plasticity afforded by this exchange mechanism may enable large variations in FBP expression during development and in FBP gene number during evolution. [Display omitted] •Cand1 promotes dynamic assembly/disassembly of SCF ubiquitin ligases•Cand1⋅Cul1⋅Dcn1 complexes are primed for neddylation upon SCF formation•Mathematical model reveals fast remodeling of the SCF repertoire in cells•Cand1 confers tolerance to large changes in the expression of F-box proteins Recruitment of specific F-box proteins to Cul1 determines the substrate specificity of Skp1⋅Cul1⋅F-box protein (SCF) ubiquitin ligases. Liu et al. revealed that Cand1/2 enables Cul1 to rapidly sample the entire pool of F-box proteins, ensuring timely ubiquitination of SCF substrates and tolerance against variation in F-box protein expression.