RBR ligase-mediated ubiquitin transfer: a tale with many twists and turns

RBR ligases are an enigmatic class of E3 ubiquitin ligases that combine properties of RING and HECT-type Epsilon 3s and undergo multilevel regulation through autoinhibition, post-translational modifications, multimerization and interaction with binding partners. Here, we summarize recent progress in RBR structures and function, which has uncovered commonalities in the mechanisms by which different family members transfer ubiquitin through a multistep process. However, these studies have also highlighted clear differences in the activity of different family members, suggesting that each RBR ligase has evolved specific properties to fit the biological process it regulates.