Abstract
The RBR (RING-BetweenRING-RING) or TRIAD [two RING fingers and a DRIL (double RING finger linked)] E3 ubiquitin ligases comprise a group of 12 complex multidomain enzymes. This unique family of E3 ligases includes parkin, whose dysfunction is linked to the pathogenesis of early-onset Parkinson's disease, and HOIP (HOIL-1-interacting protein) and HOIL-1 (haem-oxidized IRP2 ubiquitin ligase 1), members of the LUBAC (linear ubiquitin chain assembly complex). The RBR E3 ligases share common features with both the larger RING and HECT (homologous with E6-associated protein C-terminus) E3 ligase families, directly catalysing ubiquitin transfer from an intrinsic catalytic cysteine housed in the C-terminal domain, as well as recruiting thioester-bound E2 enzymes via a RING domain. Recent three-dimensional structures and biochemical findings of the RBRs have revealed novel protein domain folds not previously envisioned and some surprising modes of regulation that have raised many questions. This has required renaming two of the domains in the RBR E3 ligases to more accurately reflect their structures and functions: the C-terminal Rcat (required-for-catalysis) domain, essential for catalytic activity, and a central BRcat (benign-catalytic) domain that adopts the same fold as the Rcat, but lacks a catalytic cysteine residue and ubiquitination activity. The present review discusses how three-dimensional structures of RBR (RING1-BRcat-Rcat) E3 ligases have provided new insights into our understanding of the biochemical mechanisms of these important enzymes in ubiquitin biology.
Highlights
The post-translational modification of proteins with the covalent attachment of the 76-residue protein ubiquitin is a critical event that determines the fate of many proteins in the cell
Numerous additional protein–protein interaction domains in the RBRs have been predicted including a PUB (PNGase/UBAor UBX-containing domain; for binding to ATPase domaincontaining proteins [40]), two ankyrin repeats in ankyrin repeat- and IBR domain-containing 1 (ANKIB1), an Nterminal RWD (RING finger and WD repeat-containing) domain in ARA54 [ known as RNF14 (RING finger protein 14)], as well as a conserved CPH [Cul7, parkin-like cytoplasmic p53-binding protein (Parc) and HERC2 proteins] domain involved in p53 binding [41] and a DOC domain in Parc
Parkin-mediated turnover of RAN-binding protein 2 (RanBP2) directly affects the intracellular levels of the SUMOylated histone deacetylase HDAC4 [78], an enzyme involved in DNA packing and transcriptional regulation
Summary
The RBR (RING-BetweenRING-RING) or TRIAD [two RING fingers and a DRIL (double RING finger linked)] E3 ubiquitin ligases comprise a group of 12 complex multidomain enzymes. Recent three-dimensional structures and biochemical findings of the RBRs have revealed novel protein domain folds not previously envisioned and some surprising modes of regulation that have raised many questions. This has required renaming two of the domains in the RBR E3 ligases to more accurately reflect their structures and functions: the C-terminal Rcat (required-forcatalysis) domain, essential for catalytic activity, and a central BRcat (benign-catalytic) domain that adopts the same fold as the Rcat, but lacks a catalytic cysteine residue and ubiquitination activity.
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