| Primary Identifier | IPR044066 | Type | Domain |
| Short Name | TRIAD_supradom |
| description | The TRIAD (Two RING fingers and a DRIL, double RING finger linked) or RBR (RING-BetweenRING-RING) family of zinc finger proteins contains a tripartite motif of three double zinc fingers, the first of which, RING1, is a typical RING finger with a C3HC4 signature of conserved cysteine and histidine residues. The second (In-Between-Ring, IBR, BetweenRING or DRIL) and third (RING2) are dissimilar to RINGs but share notable similarity, as they have similar spacing of cysteines and some conserved residues. The cysteine and histidine rich TRIAD domain architecture is highly conserved and found mostly in eukaryotes. TRIAD E3 ligases (E3s) are complicated multi-domain enzymes that contain a variety of domains in addition to their TRIAD supradomain. The three fingers that define the TRIAD supradomain always appear in the same order RING1-IBR-RING2, but the position of the supradomain itself relative to other domains varies. All characterised proteins containing the TRIAD supradomain have been found to possess E3 ligase activity. TRIAD E3s differ fundamentally from their eponymous RING E3 cousins by virtue of their possessing an active site, a feature lacking in all RING-type E3s. Similar to canonical RINGs, the RING1 finger of the TRIAD supradomain binds E2s loaded with Ub (E2-Ubs). However, RING2s contain an essential active-site Cys that receives Ub from E2-Ub to generate a covalent E3-Ub intermediate [, , , ].The three fingers coordinates two Zn ions. RING1 is the only domain with a classical C3HC4 cross-brace zinc-coordination topology. IBR and RING2 fingers do not only share structural similarity but also have a completely distinct topology from classical RINGs. The IBR finger adopts a bilobal fold about the two zinc-binding sites. This arrangement brings the N-terminal of the domain within close proximity to its C-terminal. The RING2 has the same domain topology as the IBR finger and coordinates its two zinc atoms in a sequential fashion. The RING2 finger contains a conserved Cys residue that is not involved in Zn coordination but serves as the active site to which Ub is attached. While they resemble RING2s in topology, IBR fingers do not contain an active-site Cys. IBRs and their linkers on either side have been implicated in binding Ub during Ub transfer reactions, but the exact function of IBRs remains unknown [, , , ].This entry represents the TRIAD supradomain found in a number of proteins with different functions, such as Ariadne (ARI) proteins, implicated in the regulation of translation, cellular proliferation, and developmental processes; TRIAD proteins, associated with the regulation of myeloid progenitors proliferation, NF-kappaB signaling, and membrane trafficking or Parkin, implicated in a range of biological processes, including autophagy of damaged mitochondria (mitophagy), cell survival pathways, and vesicle trafficking. This supradomain is also present in heme-oxidized IRP2 ubiquitin ligase 1L (HOIL-1L) and HOIL-1L interacting protein (HOIP) which form the two linear ubiquitin chain assembly complex (LUBAC), associated with B-cell function, regulation of apoptosis, oncogenesis, and diverse autoimmune diseases. |
