Characterization of the Cullin7 E3 ubiquitin ligase--heterodimerization of cullin substrate receptors as a novel mechanism to regulate cullin E3 ligase activity

Cell Signal. 2012 Jan;24(1):290-5. doi: 10.1016/j.cellsig.2011.08.020. Epub 2011 Sep 16.

Abstract

Cul1 and Cul7 are cullin E3 ubiquitin ligase scaffold proteins. Cul1 is known to form a complex with the RING domain protein Rbx1 and one of approximately 70 different F-box proteins. F-box proteins function as substrate receptor subunits and recruit numerous substrates for poly-ubiquitination. Similarly to Cul1, Cul7 interacts with Rbx1, however, only one F-box protein, Fbxw8, has been shown to bind to Cul7. To date only few Cul7 E3 ubiquitin ligase substrates, including cyclin D1, IRS-1 and GRASP65, have been reported, and using Fbxw8 affinity purification, we were unable to identify additional substrate proteins. Here we provide evidence for a model in which Cul7-Rbx1 can promote the ubiquitination of Cul1 substrates by forming high order complexes with Cul1-Rbx1. Binding of Cul1-Rbx1 to Cul7-Rbx1 is mediated via heterodimerization of Fbxw8 with other F-box proteins which function to recruit substrates into the E3 ligase complex. The formation of this high order complex is likely to increase polyubiquitination efficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cullin Proteins / metabolism*
  • F-Box Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Leupeptins / pharmacology
  • Multiprotein Complexes / metabolism
  • NEDD8 Protein
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Protein Binding
  • Protein Multimerization*
  • Protein Processing, Post-Translational*
  • Protein Stability
  • Protein Structure, Tertiary
  • Proteolysis
  • Recombinant Fusion Proteins / metabolism
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Ubiquitination
  • Ubiquitins / metabolism
  • beta Catenin / metabolism

Substances

  • CUL7 protein, human
  • Cullin 1
  • Cullin Proteins
  • F-Box Proteins
  • FBXW8 protein, human
  • Leupeptins
  • Multiprotein Complexes
  • NEDD8 Protein
  • NEDD8 protein, human
  • Proteasome Inhibitors
  • Recombinant Fusion Proteins
  • Ubiquitins
  • beta Catenin
  • SKP Cullin F-Box Protein Ligases
  • Proteasome Endopeptidase Complex
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde