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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.


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.
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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.

Mentions: The bivalent geometry of the dimeric SCF structure provides different distances between a substrate-binding site and the two E2 docking sites [38] (Fig. 3B). These distinct catalytic site-to-substrate distances can allow an SCF complex to target different-sized substrates and accommodate changes in the length of the elongating polyubiquitin chain [38] (Fig. 3). For the SCFCdc4 complex, dimerization does not affect its affinity for the substrate Sic1, but is required for optimal ubiquitin chain initiation and elongation [38,44]. The in vitro ubiquitination of three of four tested SCFCdc4 substrates is more efficiently ubiquitinated by dimeric SCFCdc4 [38]. Similarly, dimeric mammalian SCFFbw7/hCdc4 can more efficiently ubiquitinate its substrate cyclin E than can monomeric SCFFbw7/hCdc4 [44]. Dimerization also provides the potential for the two SRSs in the complex to work together to bind one substrate so that it is optimally tethered for ubiquitination, as has been proposed for the dimeric CRL3Keap1 complex binding to its substrate Nrf2 [46].


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

Bosu DR, Kipreos ET - Cell Div (2008)

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

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

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.
Mentions: The bivalent geometry of the dimeric SCF structure provides different distances between a substrate-binding site and the two E2 docking sites [38] (Fig. 3B). These distinct catalytic site-to-substrate distances can allow an SCF complex to target different-sized substrates and accommodate changes in the length of the elongating polyubiquitin chain [38] (Fig. 3). For the SCFCdc4 complex, dimerization does not affect its affinity for the substrate Sic1, but is required for optimal ubiquitin chain initiation and elongation [38,44]. The in vitro ubiquitination of three of four tested SCFCdc4 substrates is more efficiently ubiquitinated by dimeric SCFCdc4 [38]. Similarly, dimeric mammalian SCFFbw7/hCdc4 can more efficiently ubiquitinate its substrate cyclin E than can monomeric SCFFbw7/hCdc4 [44]. Dimerization also provides the potential for the two SRSs in the complex to work together to bind one substrate so that it is optimally tethered for ubiquitination, as has been proposed for the dimeric CRL3Keap1 complex binding to its substrate Nrf2 [46].

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.