SCF E3 complex

Elucidation of the structure of the SCF ubiquitin E3 ligase complex and their substrates should help resolve certain issues regarding the mechanism by which SCF E3 ligase promotes ubiquitin transfer from the E2 enzyme to the protein substrate. Recently, the structures of Cull/Rocl in complex with Skpl and Skp2, as well as that of Skpl/jS-Trcp and Cdc4, have been reported [21, 25, 55, 56]. These studies... 

The SCF and SCF-like complexes are multi-subunit RING-type E3s that represent the largest E3 family knotvn to date. This superfamily of E3s are involved in regulating cell-cycle progression, signal transduction pathways, transcriptional control, and multiple aspects of cell growth and development (reviewed in Ref. [50]). All members of this E3 superfamily contain two basic components, a member of the cullin protein family and a RING-domain protein. The cullin subumt serves as the... 

Even with the uncertainty in E2 active-site position, the models have suggested that there would be no E3 residues near the E2 active site, in agreement with the observations made in the c-Cbl-E2 structure. This again ruled out the possibility that the SCF E3 provides acid/base catalysis and the possibility that the SCF positions the -amino group of the lysine at the E2 active site [66]. The only plausible mechanism left accounting for the catalysis mediated by the SCF in substrate ubiq-uitination is that the E3 complex helps increase the effective concentration of a portion of the substrate that contains the physiological ubiquitination-site lysine at the E2 active site. This model made the testable prediction that the distance between the destruction motif and the ubiquitinated lysine is a determinant of the ubiquiti-nation efficiency. 

Two types of E2/E3 complexes are of particular importance for cell cycle control. One complex, the SCF complex, is of outstanding importance for the Gl/S transition. The other, the anaphase-promoting complex or the cyclosome, is especially important for the course and control of mitosis. Common to both complexes is the variable collaboration with different proteins to mediate the ubiquitinylation of different substrates. 

The SCF, a ubiquitin ligase complex, consists of the piimaiy subunits Skpl, Cullin and Rbx/Rocl. While the Rbx/Cul components form the E3 ligase catalytic core... 

The essential components of the SCF ubiquitin E3 ligase include Skpl, Cul-1/ Cdc53, one of many F-box proteins, and the RINC-H2-finger protein Rod (Rbxl or Hrtl) (Figure 6.2). Although initial studies did not reveal the presence of a fourth component of the SCF complex [14, 15], later work showed that a RINC-H2-finger protein, Rod, is an essential subunit of the SCF complex [3]. The SCF complex thus contains three invariable components (Rod, Cull, and Skpl) which provide a core structure to which one of the many substrate-specific subunits (F-box proteins) binds. The Rocl-Cull-Skpl core also independently interacts with the ubiquitin E2-conjugating enzyme to couple ubiquitin transfer to the substrates [3]. One of the E-box proteins binds directly to a specific substrate and such interaction facilitates the polyubiquitination of the substrate by ubiquitin... 

Fig. 6.2. The structures of SCF, Cul2-Elongin B-C, and Cul3-BTB/POZ ubiquitin E3 ligase complexes with the bound substrates and E2 enzymes.

The SCF Complex and the Related Cullin-containing Ubiquitin E3 Ligase 1151... 

---