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

Mol Cell. 2018 Mar 1;69(5):773-786.e6. 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.

Keywords: Cand1; SCF cycle; exchange factor; mathematical modeling; ubiquitin ligase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cullin Proteins / chemistry
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism
  • F-Box Proteins* / biosynthesis
  • F-Box Proteins* / chemistry
  • F-Box Proteins* / genetics
  • Gene Expression Regulation*
  • Mice
  • Models, Biological*
  • Models, Chemical*
  • NEDD8 Protein / chemistry
  • NEDD8 Protein / genetics
  • NEDD8 Protein / metabolism
  • Proteolysis*
  • Transcription Factors* / chemistry
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism


  • Cullin 1
  • Cullin Proteins
  • F-Box Proteins
  • NEDD8 Protein
  • Nedd8 protein, mouse
  • TIP120 protein, mouse
  • Transcription Factors