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

License
getmorefigures.php?uid=PMC2266742&req=5

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.

Mentions: Recently it has become apparent that a number of CRL complexes function as dimers. CUL1, CUL3 and CUL4-based CRL complexes have been observed to form dimers or multimers in vivo [36-38]. In contrast, CUL2 and CUL5 CRL complexes have only been observed as monomers [36]. There are two potential mechanisms of dimerization: SRS-mediated dimerization (which has been demonstrated for SCF complexes); and a Nedd8-cullin linkage (which has been demonstrated for CUL3 CRL complexes). SRS-mediated dimerization relies on binding between SRS proteins to link together two CRL complexes. Multiple F-box proteins have been observed to form dimers in vivo, including Fbw7, Pop1 & Pop2, Cdc4, Met30, Skp2, and βTrcp1 & βTrcp2 [39-45]. Dimerization of F-box proteins is initiated through a conserved D-domain located immediately N-terminal of the F-box motif [38,42,44]. Analysis of SCFCdc4 complexes by small angle X-ray scatter analysis indicates that the two substrate-binding sites of the SRSs and the two E2-binding sites form a coplanar surface in a suprafacial orientation [38] (Fig. 2A).


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

Bosu DR, Kipreos ET - Cell Div (2008)

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

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

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.
Mentions: Recently it has become apparent that a number of CRL complexes function as dimers. CUL1, CUL3 and CUL4-based CRL complexes have been observed to form dimers or multimers in vivo [36-38]. In contrast, CUL2 and CUL5 CRL complexes have only been observed as monomers [36]. There are two potential mechanisms of dimerization: SRS-mediated dimerization (which has been demonstrated for SCF complexes); and a Nedd8-cullin linkage (which has been demonstrated for CUL3 CRL complexes). SRS-mediated dimerization relies on binding between SRS proteins to link together two CRL complexes. Multiple F-box proteins have been observed to form dimers in vivo, including Fbw7, Pop1 & Pop2, Cdc4, Met30, Skp2, and βTrcp1 & βTrcp2 [39-45]. Dimerization of F-box proteins is initiated through a conserved D-domain located immediately N-terminal of the F-box motif [38,42,44]. Analysis of SCFCdc4 complexes by small angle X-ray scatter analysis indicates that the two substrate-binding sites of the SRSs and the two E2-binding sites form a coplanar surface in a suprafacial orientation [38] (Fig. 2A).

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.