Cand1-Mediated Adaptive Exchange Mechanism Enables Variation in F-Box Protein Expression.
Mol Cell
; 69(5): 773-786.e6, 2018 03 01.
Article
in En
| MEDLINE
| ID: mdl-29499133
ABSTRACT
Skp1â
Cul1â
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Transcription Factors
/
Gene Expression Regulation
/
F-Box Proteins
/
Proteolysis
/
Models, Biological
/
Models, Chemical
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Mol Cell
Journal subject:
BIOLOGIA MOLECULAR
Year:
2018
Type:
Article
Affiliation country:
United States