Function and regulation of cullin–RING ubiquitin ligases

Abstract

The cullin–RING ligases (CRLs) comprise a superfamily of ubiquitin ligases that are implicated in the regulation of a diverse array of eukaryotic functions. The various cullin proteins function as a rigid scaffold for the assembly of this modular class of ligase. All cullins associate with a RING protein through their C-terminal domain, whereas the N-terminal region recruits a wide variety of receptor proteins that confer substrate specificity. The cullin–RING module is often referred to as the catalytic core, because it is common to all CRLs. It recruits ubiquitin-conjugating enzymes (E2s) and activates the transfer of ubiquitin from the E2 to the substrate through an as-yet-unclear mechanism that does not involve a CRL–ubiquitin-thioester intermediate. The substrate receptors for CRLs are generally linked to the catalytic core through adaptor proteins that are specific for each cullin-family member. Numerous substrate receptors can be recruited to each CRL core, which increases the diversity of proteins that can be targeted for ubiquitylation. In most cases, the recognition of a substrate by a CRL requires post-translational modification of the substrate. This further increases the repertoire of substrates that can be targeted to a given CRL and also links protein ubiquitylation and turnover to numerous signalling pathways. CRL activity can be regulated by numerous mechanisms, which include the turnover of substrate receptors, the reversible attachment of the ubiquitin-like protein NEDD8 to cullins, and the sequestration of cullins by CAND1.