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.
- ubiquitin ligase
Abbreviations: ANKIB1, ankyrin repeat- and IBR domain-containing 1; BRcat, benign-catalytic; CCCP, carbonyl cyanide m-chlorophenylhydrazone; Cdk5, cyclin-dependent kinase 5; cIAP2, cellular inhibitor of apoptosis 2; CK1, casein kinase 1; CPH, Cul7, Parc and HERC2 proteins; CRL, Cul-RING-ligase; Cul, cullin; Eps15, epidermal growth factor receptor pathway substrate 15; FANCL, Fanconi anaemia, complementation group L; HDAC, histone deacetylase; HECT, homologous with E6-associated protein C-terminus; HOIL-1, haem-oxidized IRP2 ubiquitin ligase 1; HOIP, HOIL-1-interacting protein; IBR, InBetweenRING; LUBAC, linear ubiquitin chain assembly complex; MDM2, murine double minute 2; MIRO, mitochondrial Rho GTPase; NEDD, neural-precursor-cell-expressed developmentally down-regulated; NEMO, NF-κB essential modulator; NF-κB, nuclear factor κB; NZF, Npl4 ZNF; Parc, parkin-like cytoplasmic p53-binding protein; PINK1, PTEN-induced putative kinase 1; PKC, protein kinase C; RanBP2, RAN-binding protein 2; RBR, RING-BetweenRING-RING/RING1-BRcat-Rcat; Rcat, required-for-catalysis; RNF, RING finger protein; RWD, RING finger and WD repeat-containing; SH3, Src homology 3; SHARPIN, SHANK-associated RH domain interactor; SILAC, stable isotope labelling by amino acids in cell culture; SUMO, small ubiquitin-related modifier; TOMM70A, translocase of outer mitochondrial membrane 70 homologue A; TRAF6, tumour-necrosis-factor-receptor-associated factor 6; TRIAD, two RING fingers and a DRIL (double RING finger linked); UBA, ubiquitin-associated; UBE2L, ubiquitin-conjugating enzyme E2L; UIM, ubiquitin-interacting motif; Ubl, ubiquitin-like; ZNF, zinc finger
- © 2014 The author(s)