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.