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CAND1 controls in vivo dynamics of the cullin 1-RING ubiquitin ligase repertoire.

The combinatorial architecture of cullin 1-RING ubiquitin ligases, in which multiple F-box containing substrate receptors compete for access to CUL1, poses special challenges to assembling cullin 1-RING ubiquitin ligase complexes through high affinity protein interactions while maintaining the flexibility to dynamically sample the entire F-box containing substrate receptor repertoire. Here, using highly quantitative mass spectrometry, we demonstrate that this problem is addressed by CAND1, a factor that controls the dynamics of the global cullin 1-RING ubiquitin ligase network by promoting the assembly of newly synthesized F-box containing substrate receptors with CUL1-RBX1 core complexes. Our studies of in vivo cullin 1-RING ubiquitin ligase dynamics and in vitro biochemical findings showing that CAND1 can displace F-box containing substrate receptors from Cul1p suggest that CAND1 functions in a cycle that serves to exchange F-box containing substrate receptors on CUL1 cores. We propose that this cycle assures comprehensive sampling of the entire F-box containing substrate receptor repertoire in order to maintain the cullin 1-RING ubiquitin ligase landscape, a function that we show to be critical for substrate degradation and normal physiology.

Pubmed ID: 23535663

Authors

  • Wu S
  • Zhu W
  • Nhan T
  • Toth JI
  • Petroski MD
  • Wolf DA

Journal

Nature communications

Publication Data

March 28, 2013

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM59780
  • Agency: NCI NIH HHS, Id: P20 CA132386
  • Agency: NCI NIH HHS, Id: P20 CA132386-03
  • Agency: NCI NIH HHS, Id: P30 CA030199
  • Agency: NIGMS NIH HHS, Id: P50 GM085764
  • Agency: NIGMS NIH HHS, Id: P50 GM085764
  • Agency: NIGMS NIH HHS, Id: R01 GM059780

Mesh Terms

  • Proteolysis
  • SKP Cullin F-Box Protein Ligases
  • Schizosaccharomyces
  • Schizosaccharomyces pombe Proteins
  • Substrate Specificity