Similar but Different: RBR E3 Ligases and their Domains that are Crucial for Function

Abstract

Background: The E3 ubiquitin ligases can be subdivided into four distinct types (RING, HECT, U-box, and RBR type) based on their domain architecture and ubiquitin transfer mechanism. Recent structures of different RBR E3 ligases have been solved showing enzymes in their autoinhibited state. The only exception is HOIP/ HOIL-1L which was recently solved in its “active” conformation. This review discusses the structural and functional characteristics of three different members of the RBR E3 ubiquitin ligase family: Parkin, HOIP/HOIL-1L, and HHARI.

Methods: Searches were performed using PubMed. Search term includes “RBR E3 Ligase”, “Parkin”, “HOIP/ HOIL-1L”, “HHARI”, “UbcH7”, and “E2”. In the end, 25 journal articles were selected as the foundation of this review. The structural coordinates of Parkin, HOIP, and HHARI were accessed from the PDB (www.rcsb.org) with the PDB IDs 4ZYN, 5EDV, and 4KBL, respectively.

Summary: Currently, most solved RBR E3 ligase structures are only in their inactive forms, except for HOIP/ HOIL-1L, and these inactive forms provide valuable information on how these proteins are regulated in vivo. All the RBR E3 ligases have common domains, but their structures and functions are heavily dependent on their accessory domains, which serve as regulators that orchestrate certain ubiquitin chain syntheses and play a role in the autoinhibition of RBR E3 ligases. Although these domains are structurally different, they use distinct molecular interactions to achieve the same goal. While the regulation of most RBR E3 ligases has been extensively studied, more structural studies are required to further characterize the mechanism that these enzymes use to build different ubiquitin chains. Understanding the mechanisms underlying the formation of each type of ubiquitin chain could help elucidate their functions and related pathways.