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Cullin-RING ubiquitin ligases: global regulation and activation cycles.

Bosu DR, Kipreos ET - Cell Div (2008)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cellular Biology, University of Georgia, 724 Biological Sciences Bldg,, Athens, GA 30602-2607, USA. ekipreos@cb.uga.edu.

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.

No MeSH data available.


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.
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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.

Mentions: The most intensively studied cullin is metazoan CUL1 and its budding yeast ortholog Cdc53. CUL1 and Cdc53-based CRLs are called SCF complexes, and contain four subunits: Skp1; CUL1 (Cdc53); an F-box protein; and the RING H2 finger protein Rbx1/Roc1/Hrt1 [7]. The crystal structure of the SCF complex reveals that the cullin acts as a rigid backbone for the assembly of the complex [11,12] (Fig. 1A). The CUL1 C-terminus binds Rbx1 and the N-terminus binds the adaptor Skp1. Rbx1 facilitates the recruitment of the E2 to the complex [13]. The adaptor Skp1 binds the SRS, which is an F-box protein that links to Skp1 through the F-box motif. The F-box protein binds and positions the substrate for ubiquitination by the E2. The combination of distinct F-box proteins with the core components creates unique SCF complexes that bind distinct sets of substrates. Metazoan genomes contain a relatively large number of genes encoding F-box proteins, e.g., humans have ~70 F-box proteins, while C. elegans has over 300 [14,15]. Many uncharacterized yeast and mammalian F-box proteins are capable of forming SCF complexes in vitro, suggesting the existence of a large number of SCF complexes [16,17]. F-box proteins generally bind to phosphorylated residues on substrates, and therefore, substrate degradation by SCF complexes is regulated by phosphorylation [7].


Cullin-RING ubiquitin ligases: global regulation and activation cycles.

Bosu DR, Kipreos ET - Cell Div (2008)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2266742&req=5

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.
Mentions: The most intensively studied cullin is metazoan CUL1 and its budding yeast ortholog Cdc53. CUL1 and Cdc53-based CRLs are called SCF complexes, and contain four subunits: Skp1; CUL1 (Cdc53); an F-box protein; and the RING H2 finger protein Rbx1/Roc1/Hrt1 [7]. The crystal structure of the SCF complex reveals that the cullin acts as a rigid backbone for the assembly of the complex [11,12] (Fig. 1A). The CUL1 C-terminus binds Rbx1 and the N-terminus binds the adaptor Skp1. Rbx1 facilitates the recruitment of the E2 to the complex [13]. The adaptor Skp1 binds the SRS, which is an F-box protein that links to Skp1 through the F-box motif. The F-box protein binds and positions the substrate for ubiquitination by the E2. The combination of distinct F-box proteins with the core components creates unique SCF complexes that bind distinct sets of substrates. Metazoan genomes contain a relatively large number of genes encoding F-box proteins, e.g., humans have ~70 F-box proteins, while C. elegans has over 300 [14,15]. Many uncharacterized yeast and mammalian F-box proteins are capable of forming SCF complexes in vitro, suggesting the existence of a large number of SCF complexes [16,17]. F-box proteins generally bind to phosphorylated residues on substrates, and therefore, substrate degradation by SCF complexes is regulated by phosphorylation [7].

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cellular Biology, University of Georgia, 724 Biological Sciences Bldg,, Athens, GA 30602-2607, USA. ekipreos@cb.uga.edu.

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.

No MeSH data available.