Twists and Turns in Ubiquitin Conjugation Cascades

Abstract

Post‐translational modification by ubiquitin‐like proteins (UBLs) is a predominant eukaryotic regulatory mechanism. The vast reach of this form of regulation extends to virtually all eukaryotic processes that involve proteins. UBL modifications play critical roles in controlling the cell cycle, transcription, DNA repair, stress responses, signaling, immunity, plant growth, embryogenesis, circadian rhythms, and a plethora of other pathways. UBLs dynamically modulate target protein properties including enzymatic activity, conformation, half‐life, subcellular localization, and intermolecular interactions. Moreover, the enzymatic process of UBL ligation to proteins is itself dynamic, involving cascades of E1, E2, and E3 enzymes. The UBL C‐terminus is first activated, then transferred between multiple enzyme active sites, and ultimately ligated via an E3 enzyme to a target. With roughly 300 members, the largest E3 family consists of Cullin‐RING ligases (CRLs), which regulate a staggering number of biochemical pathways and biological processes. In my presentation, I will discuss recent results from the lab addressing structural mechanisms underlying regulation of and by this large family of dynamic ubiquitin E3 ligases.