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All change: protein conformation and the ubiquitination reaction cascade.

Riedinger C, Endicott JA - F1000 Biol Rep (2009)

Bottom Line: The structures of enzymes that collectively modify proteins by covalent addition of ubiquitin-like protein moieties have provided significant insights into the regulatory pathways they compose and have highlighted the importance of protein flexibility for the mechanism and regulation of the ubiquitination reaction.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biophysics and Department of Biochemistry South Parks Road, Oxford OX1 3QU UK.

ABSTRACT
The structures of enzymes that collectively modify proteins by covalent addition of ubiquitin-like protein moieties have provided significant insights into the regulatory pathways they compose and have highlighted the importance of protein flexibility for the mechanism and regulation of the ubiquitination reaction.

No MeSH data available.


Conformational change accompanies catalysis in E3s(a) Model for an E2/SCFSkp2 complex. This image was generated by merging the structures of Cul1-Rbx1-Skp1-Skp2 (1LDK) [14] and Skp1/Skp2 (1FQV) [20] as described in [14]. The E2 UbcH7 (2FBV) was then placed on to the Rbx1 RING domain guided by the c-Cbl-UbcH7 structure [21]. Skp1 and Skp2 are shown in blue and yellow (respectively), Cul1 in dark grey, Rbx1 in dark red, and the E2 UbcH7 in cyan. The catalytic cysteine is coloured pink. (b) Conformational change accompanies neddylation of Cul1. The panels highlight the change in the association of Rbx1 with Cul1 that accompanies Cul1 neddylation (dark red arrow). For comparison, only the Cul1 C-terminal domain (dark grey) is drawn. The left panel shows the non-neddylated structure in which Rbx1 (dark red ribbon) forms a close association with Cul1. Lys724 (non-neddylated) is drawn as blue spheres. The right panel depicts the neddylated Cul1-Rbx1 complex. Neddylation (NEDD8, red) promotes a more open Cul1-Rbx1 association. Lys724 covalently bound to NEDD8 is drawn as blue spheres. Cul1, cullin 1; NEDD8, neural precursor cell expressed, developmentally downregulated 8; Rbx1, RIGG-box protein 1; RING, really interesting new gene; SCF, Skp1 [S-phase kinase-associated protein 1]-cullin-F box; Skp, S-phase kinase-associated protein.
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fig-002: Conformational change accompanies catalysis in E3s(a) Model for an E2/SCFSkp2 complex. This image was generated by merging the structures of Cul1-Rbx1-Skp1-Skp2 (1LDK) [14] and Skp1/Skp2 (1FQV) [20] as described in [14]. The E2 UbcH7 (2FBV) was then placed on to the Rbx1 RING domain guided by the c-Cbl-UbcH7 structure [21]. Skp1 and Skp2 are shown in blue and yellow (respectively), Cul1 in dark grey, Rbx1 in dark red, and the E2 UbcH7 in cyan. The catalytic cysteine is coloured pink. (b) Conformational change accompanies neddylation of Cul1. The panels highlight the change in the association of Rbx1 with Cul1 that accompanies Cul1 neddylation (dark red arrow). For comparison, only the Cul1 C-terminal domain (dark grey) is drawn. The left panel shows the non-neddylated structure in which Rbx1 (dark red ribbon) forms a close association with Cul1. Lys724 (non-neddylated) is drawn as blue spheres. The right panel depicts the neddylated Cul1-Rbx1 complex. Neddylation (NEDD8, red) promotes a more open Cul1-Rbx1 association. Lys724 covalently bound to NEDD8 is drawn as blue spheres. Cul1, cullin 1; NEDD8, neural precursor cell expressed, developmentally downregulated 8; Rbx1, RIGG-box protein 1; RING, really interesting new gene; SCF, Skp1 [S-phase kinase-associated protein 1]-cullin-F box; Skp, S-phase kinase-associated protein.

Mentions: A particular example, well documented by structural studies, is that of the SCF [Skp1 (S-phase kinase-associated protein 1)-cullin-F box] E3 Ub ligase family (reviewed in [13]). This E3 contains a RING domain that binds to the cullin subunit. The cullin functions as a scaffold within the complex and also binds to the adaptor protein Skp1 [14]. SCF activity is promoted by cullin neddylation [15] and inhibited by CAND1 (cullin-associated and neddylation-dissociated 1) binding [16]. Skp1 and the cullin together mediate the interaction between a diverse set of F-box-containing proteins that bring substrates to the E2, and E3 catalytic core. Models for SCF E3/E2 complexes have been constructed by superimposing structures of selected subcomplexes [14,17] (Figure 2a). However, it is difficult to see how catalysis will proceed as the E3 substrate bound to its cognate F-box protein is located approximately 50 Å away from the bound activated E2-Ubl [14].


All change: protein conformation and the ubiquitination reaction cascade.

Riedinger C, Endicott JA - F1000 Biol Rep (2009)

Conformational change accompanies catalysis in E3s(a) Model for an E2/SCFSkp2 complex. This image was generated by merging the structures of Cul1-Rbx1-Skp1-Skp2 (1LDK) [14] and Skp1/Skp2 (1FQV) [20] as described in [14]. The E2 UbcH7 (2FBV) was then placed on to the Rbx1 RING domain guided by the c-Cbl-UbcH7 structure [21]. Skp1 and Skp2 are shown in blue and yellow (respectively), Cul1 in dark grey, Rbx1 in dark red, and the E2 UbcH7 in cyan. The catalytic cysteine is coloured pink. (b) Conformational change accompanies neddylation of Cul1. The panels highlight the change in the association of Rbx1 with Cul1 that accompanies Cul1 neddylation (dark red arrow). For comparison, only the Cul1 C-terminal domain (dark grey) is drawn. The left panel shows the non-neddylated structure in which Rbx1 (dark red ribbon) forms a close association with Cul1. Lys724 (non-neddylated) is drawn as blue spheres. The right panel depicts the neddylated Cul1-Rbx1 complex. Neddylation (NEDD8, red) promotes a more open Cul1-Rbx1 association. Lys724 covalently bound to NEDD8 is drawn as blue spheres. Cul1, cullin 1; NEDD8, neural precursor cell expressed, developmentally downregulated 8; Rbx1, RIGG-box protein 1; RING, really interesting new gene; SCF, Skp1 [S-phase kinase-associated protein 1]-cullin-F box; Skp, S-phase kinase-associated protein.
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fig-002: Conformational change accompanies catalysis in E3s(a) Model for an E2/SCFSkp2 complex. This image was generated by merging the structures of Cul1-Rbx1-Skp1-Skp2 (1LDK) [14] and Skp1/Skp2 (1FQV) [20] as described in [14]. The E2 UbcH7 (2FBV) was then placed on to the Rbx1 RING domain guided by the c-Cbl-UbcH7 structure [21]. Skp1 and Skp2 are shown in blue and yellow (respectively), Cul1 in dark grey, Rbx1 in dark red, and the E2 UbcH7 in cyan. The catalytic cysteine is coloured pink. (b) Conformational change accompanies neddylation of Cul1. The panels highlight the change in the association of Rbx1 with Cul1 that accompanies Cul1 neddylation (dark red arrow). For comparison, only the Cul1 C-terminal domain (dark grey) is drawn. The left panel shows the non-neddylated structure in which Rbx1 (dark red ribbon) forms a close association with Cul1. Lys724 (non-neddylated) is drawn as blue spheres. The right panel depicts the neddylated Cul1-Rbx1 complex. Neddylation (NEDD8, red) promotes a more open Cul1-Rbx1 association. Lys724 covalently bound to NEDD8 is drawn as blue spheres. Cul1, cullin 1; NEDD8, neural precursor cell expressed, developmentally downregulated 8; Rbx1, RIGG-box protein 1; RING, really interesting new gene; SCF, Skp1 [S-phase kinase-associated protein 1]-cullin-F box; Skp, S-phase kinase-associated protein.
Mentions: A particular example, well documented by structural studies, is that of the SCF [Skp1 (S-phase kinase-associated protein 1)-cullin-F box] E3 Ub ligase family (reviewed in [13]). This E3 contains a RING domain that binds to the cullin subunit. The cullin functions as a scaffold within the complex and also binds to the adaptor protein Skp1 [14]. SCF activity is promoted by cullin neddylation [15] and inhibited by CAND1 (cullin-associated and neddylation-dissociated 1) binding [16]. Skp1 and the cullin together mediate the interaction between a diverse set of F-box-containing proteins that bring substrates to the E2, and E3 catalytic core. Models for SCF E3/E2 complexes have been constructed by superimposing structures of selected subcomplexes [14,17] (Figure 2a). However, it is difficult to see how catalysis will proceed as the E3 substrate bound to its cognate F-box protein is located approximately 50 Å away from the bound activated E2-Ubl [14].

Bottom Line: The structures of enzymes that collectively modify proteins by covalent addition of ubiquitin-like protein moieties have provided significant insights into the regulatory pathways they compose and have highlighted the importance of protein flexibility for the mechanism and regulation of the ubiquitination reaction.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biophysics and Department of Biochemistry South Parks Road, Oxford OX1 3QU UK.

ABSTRACT
The structures of enzymes that collectively modify proteins by covalent addition of ubiquitin-like protein moieties have provided significant insights into the regulatory pathways they compose and have highlighted the importance of protein flexibility for the mechanism and regulation of the ubiquitination reaction.

No MeSH data available.