RBR E3-ligases at work

Abstract

The RING-in-between-RING (RBR) E3s are a curious family of ubiquitin E3-ligases, whose mechanism of action is unusual in several ways. Their activities are auto-inhibited, causing a requirement for activation by protein-protein interactions or posttranslational modifications. They catalyse ubiquitin conjugation by a concerted RING/HECT-like mechanism in which the RING1 domain facilitates E2-discharge to directly form a thioester intermediate with a cysteine in RING2. This short-lived, HECT-like intermediate then modifies the target. Uniquely, the RBR ligase HOIP makes use of this mechanism to target the ubiquitin amino-terminus, by presenting the target ubiquitin for modification using its distinctive LDD region. RBR E3 ligases are an unusual family that includes Parkin and LUBAC. Basally autoinhibited, they have a HECT-like mode of ubiquitin conjugation, and LUBAC makes linear ubiquitin chains. This Review discusses recent important insights into their structure and function. © 2014 The Authors.