Structural regulation of cullin-RING ubiquitin ligase complexes

▶ Recent structural studies have revealed numerous ways in which CRL E3 ligase activities are controlled, including: ▶ Mechanisms of multimodal CRL E3 ligase activation by covalent attachment of the ubiquitin-like protein NEDD8. ▶ A novel ‘dual E3’ mechanism for ligation of NEDD8 to cullins. ▶ Mechanism inhibition of CRL assembly/activity by CAND1. ▶ Numerous mechanisms of regulated substrate recruitment to CRLs, including via substrate post-translational modification or various forms of regulation by small molecule plant hormones. Cullin-RING ligases (CRLs) compose the largest class of E3 ubiquitin ligases. CRLs are modular, multisubunit enzymes, comprising interchangeable substrate receptors dedicated to particular Cullin-RING catalytic cores. Recent structural studies have revealed numerous ways in which CRL E3 ligase activities are controlled, including multimodal E3 ligase activation by covalent attachment of the ubiquitin-like protein NEDD8, inhibition of CRL assembly/activity by CAND1, and several mechanisms of regulated substrate recruitment. These features highlight the potential for CRL activities to be tuned in responses to diverse cellular cues, and for modulating CRL functions through small-molecule agonists or antagonists. As the second installment of a two-review series, this article focuses on recent structural studies advancing our knowledge of how CRL activities are regulated.