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

Shuangding Wu, Wenhong Zhu, Tina Nhan, Julia I. Toth, Matthew D. Petroski and Dieter A. Wolf ()
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Shuangding Wu: Signal Transduction Program, Sanford-Burnham Medical Research Institute
Wenhong Zhu: NCI Cancer Center Proteomics Facility, Sanford-Burnham Medical Research Institute
Tina Nhan: Signal Transduction Program, Sanford-Burnham Medical Research Institute
Julia I. Toth: Signal Transduction Program, Sanford-Burnham Medical Research Institute
Matthew D. Petroski: Signal Transduction Program, Sanford-Burnham Medical Research Institute
Dieter A. Wolf: Signal Transduction Program, Sanford-Burnham Medical Research Institute

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms2636

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