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. 2008 Feb 18:3:7.
doi: 10.1186/1747-1028-3-7.

Cullin-RING ubiquitin ligases: global regulation and activation cycles

Dimple R Bosu  1 , Edward T Kipreos
Affiliations

Cullin-RING ubiquitin ligases: global regulation and activation cycles

Dimple R Bosu et al. Cell Div. .

Abstract

Cullin-RING ubiquitin ligases (CRLs) comprise the largest known category of ubiquitin ligases. CRLs regulate an extensive number of dynamic cellular processes, including multiple aspects of the cell cycle, transcription, signal transduction, and development. CRLs are multisubunit complexes composed of a cullin, RING H2 finger protein, a variable substrate-recognition subunit (SRS), and for most CRLs, an adaptor that links the SRS to the complex. Eukaryotic species contain multiple cullins, with five major types in metazoa. Each cullin forms a distinct class of CRL complex, with distinct adaptors and/or substrate-recognition subunits. Despite this diversity, each of the classes of CRL complexes is subject to similar regulatory mechanisms. This review focuses on the global regulation of CRL complexes, encompassing: neddylation, deneddylation by the COP9 Signalosome (CSN), inhibitory binding by CAND1, and the dimerization of CRL complexes. We also address the role of cycles of activation and inactivation in regulating CRL activity and switching between substrate-recognition subunits.

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Figures

Figure 1
Figure 1
Structures of multisubunit CRL complexes. Diagrams of the CUL1 (A), CUL2 (B), CUL5 (C), CUL3 (D), and CUL4 (E) CRL complexes. Proteins in the complexes are labeled. The structures are described in the text.
Figure 2
Figure 2
Proposed models for dimerization of CRL complexes. (A) Diagram of an SRS-mediated dimeric SCF complex. Dimerization is mediated by interactions between the SRSs in each CRL. This structure has been experimentally confirmed [38]. (B) Diagram of a Nedd8-cullin-based dimeric CRL3 complex. Dimerization is mediated by interaction between Nedd8, which is covalently linked to one CUL3 protein, and the WH-B domain of an unneddylated CUL3 [37]. The overall structure of the Nedd8-cullin-based dimer has not been determined. The dimer is drawn in a head-to-head conformation to accommodate the binding of a dimeric SRS to the two CUL3 N-termini (as many CRL3 SRSs are constitutively dimeric in vivo). (C) Diagram of a monomeric CRL2 complex binding a dimeric SRS. The existence of such a structure has not yet been directly confirmed by experiments (see text). Proteins are labeled as in Fig. 1.
Figure 3
Figure 3
Poly-ubiquitination reactions by monomeric and dimeric SCF complexes. Diagram of poly-ubiquitin conjugation to a substrate (rectangle) by monomeric (A) and dimeric (B) SCF complexes. Top panels, E2 with activated ubiquitin prior to binding. Middle panels, E2 with activated ubiquitin loaded onto E3 but prior to transfer of ubiquitin to substrate. Bottom panels, the substrate has a three-ubiquitin chain and a new E2 with activated ubiquitin has docked. Note how the ability of E2s to load onto both sites of the dimeric SCF complex facilitates the addition of ubiquitin onto the growing polyubiquitin chain. In the diagram, the addition of the first ubiquitin is more sterically favorable from the E2 docking site that is closer to the substrate, while additions to the elongated polyubiquitin chain are more favorable from the more distant E2 docking site. Proteins are labeled as in Fig. 1.
Figure 4
Figure 4
Proposed activation cycle for an SCF complex. Diagram of a proposed SCF activation cycle. The SCF complex can shift between an active dimeric complex and a CSN-bound state in which the cullin is deneddylated and the SRS is protected from autoubiquitination (top). The mechanisms that regulate SCF interaction with CSN are not fully understood, but substrate binding may be associated with either releasing SCF from CSN or preventing SCF binding to CSN. When substrate is lacking, SCF complexes can either rebind CSN or lose their SRS due to autodegradation. Loss of the SRS (by autoubiquitination or the activity of other E3 ligases) allows deneddylation by the CSN complex. The deneddylated adaptor-cullin-Rbx1 complex can then either rebind an SRS to reform an SCF complex (horizontal arrow) or undergo sequestration by CAND1 (bottom), in which the adaptor is stripped away from cullin-Rbx1 in the process of CAND1 binding. CAND1 is released via an as yet undefined mechanism that involves cullin-Rbx1 binding either to the adaptor (shown) or an adaptor-SRS complex (not shown). The adaptor-cullin-Rbx1 complex binds an SRS dimer to form a dimeric SCF complex. Substrate binding promotes cullin neddylation to allow full activation of the SCF complex. Proteins are labeled as in Figs 1 and 2.
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