Mechanisms and function of substrate recruitment by F-box proteins

Nat Rev Mol Cell Biol. 2013 Jun;14(6):369-81. doi: 10.1038/nrm3582. Epub 2013 May 9.


S phase kinase-associated protein 1 (SKP1)-cullin 1 (CUL1)-F-box protein (SCF) ubiquitin ligase complexes use a family of F-box proteins as substrate adaptors to mediate the degradation of a large number of regulatory proteins involved in diverse processes. The dysregulation of SCF complexes and their substrates contributes to multiple pathologies. In the 14 years since the identification and annotation of the F-box protein family, the continued identification and characterization of novel substrates has greatly expanded our knowledge of the regulation of substrate targeting and the roles of F-box proteins in biological processes. Here, we focus on the evolution of our understanding of substrate recruitment by F-box proteins, the dysregulation of substrate recruitment in disease and potential avenues for F-box protein-directed disease therapies.

Publication types

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

MeSH terms

  • Animals
  • Evolution, Molecular*
  • Humans
  • Proteolysis*
  • S-Phase Kinase-Associated Proteins / genetics*
  • S-Phase Kinase-Associated Proteins / metabolism*
  • SKP Cullin F-Box Protein Ligases / genetics*
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Substrate Specificity / physiology


  • S-Phase Kinase-Associated Proteins
  • SKP1 protein, human
  • SKP Cullin F-Box Protein Ligases