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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.


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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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.

Mentions: TIP120A/CAND1 (cullin-associated and neddylation-dissociated) is an inhibitor that binds to cullin-Rbx complexes that lack both neddylation and adaptors [112-115]. CAND1 is a 120 kDa protein composed of multiple HEAT repeats. The crystal structure of human CAND1 bound to a CUL1-Rbx1 complex indicates that CAND1 wraps around the cullin, with the CAND1 N-terminus bound to the cullin C-terminus and the CAND1 C-terminus bound to the cullin N-terminus [116] (Fig. 4). CAND1 binding blocks both the adaptor binding site and the Nedd8 conjugation site.


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

Bosu DR, Kipreos ET - Cell Div (2008)

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

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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.
Mentions: TIP120A/CAND1 (cullin-associated and neddylation-dissociated) is an inhibitor that binds to cullin-Rbx complexes that lack both neddylation and adaptors [112-115]. CAND1 is a 120 kDa protein composed of multiple HEAT repeats. The crystal structure of human CAND1 bound to a CUL1-Rbx1 complex indicates that CAND1 wraps around the cullin, with the CAND1 N-terminus bound to the cullin C-terminus and the CAND1 C-terminus bound to the cullin N-terminus [116] (Fig. 4). CAND1 binding blocks both the adaptor binding site and the Nedd8 conjugation site.

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.