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

Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Nature Communications (Impact Factor: 11.47). 03/2013; 4:1642. DOI: 10.1038/ncomms2636
Source: PubMed


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.

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Available from: Dieter A. Wolf, Aug 13, 2014
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    • "That multiple FBPs can regulate cyclin D levels suggests they can independently sense and relay these signals onto the cyclin D hub, thus imparting redundancy and robustness to this important regulatory network. Downstream of the D-type cyclins/Cdk/pRb pathway, G1/S phase cyclins are also regulated by FBPs: SCF(Skp2) ubiquitinates cyclins E and A, and SCF(Fbxw7) ubiquitinates cyclin E. In these cases, proteasome-mediated degradation ensues (reviewed in [5]). The restriction point for entry into the cell cycle is clearly a major focal point for FBP regulation. "
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    • "As its name already reveals, CAND1 was identified as an interactor of non-neddylated cullins (Liu et al., 2002; Zheng et al., 2002; Oshikawa et al., 2003). Through a series of elegant experiments from at least three independent laboratories it was recently shown that CAND1 functions as a novel type of exchange factor for CRLs (Pierce et al., 2013; Wu et al., 2013; Zemla et al., 2013). In a highly quantitative and not only therefore remarkable analysis of the diverse protein–protein interactions that can take place between the subunits of SCF-type CRL complexes and CAND1, it could be shown that CAND1 can promote the disassembly of SCF complexes and that FBPs can remove CAND1 from CULLIN1 (Pierce et al., 2013; Figure 4). "
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    • "The variety of these mechanisms provides the means to upregulate required FBPs in response to intrinsic and extrinsic signals, while continually clearing those that are no longer required, ensuring that the available pool addresses the needs of the cell at any given time. The mechanism by which one FBP is ‘switched-out’ and replaced by another has recently been reported and is controlled by the ‘exchange factor’ Cand1 [27,28]. By increasing the dissociation rate of Skp1 : FBP complexes from the cullin scaffold, without affecting the kinetics of its reassembly, Cand1 keeps the spectrum of SCF activity within the cell dynamic and capable of responding to a changing cellular environment. "
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