|PROSITE documentation PDOC51873 [for PROSITE entry PS51873]|
In eukaryotes, protein ubiquitination is a key biochemical mechanism and plays a fundamental role in multiple cellular processes, such as protein homeostasis, signal transduction, development, differentiations and programmed cell death (PCD). Ubiquitination involves the sequential transfer of an ubiquitin (Ub) (see <PDOC00271>) molecule through an enzyme cascade consisting of an Ub-activating enzyme (E1) (see <PDOC00463>), an Ub-conjugating enzyme (E2) (see <PDOC00163>) and an ubiquitin ligase (E3), until an isopeptide bond is formed between the C-terminus of ubiquitin and the epsylon-amino group of a lysine residue on a substrate protein. Really interesting new gene (RING) fingers (see <PDOC00449>) are present in many ubiquitin ligases and have an essential role in facilitating the transfer of ubiquitin to the substrate. RING fingers are often found in conjunction with other cysteine-rich domains. The TRIAD (for 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, manifested in similar spacing of cysteines and some conserved residues. This is in contrast with the assignment of the third finger as belonging to a RING class C3HC4. One cause of this difference is that the histidine of the proposed RING signature is poorly conserved. On the other hand, highly conserved histidine and cysteines residues were disregarded in the first studies. The cysteine and histidine rich TRIAD domain architecture is highly conserved and found only in eukaryotes. TRIAD 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 characterized 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 [1,2,3,4].
Each of the three fingers coordinates two Zn(2+) ions. RING1 is the only domain with a classical C3HC4 cross-brace zinc-coordination topology typical of other RING fingers (see <PDB:4K7D>). 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 (see <PDB:2JMO>). This arrangement brings the N-terminus of the domain within close proximity to its C-terminus. The RING2 has the same domain topology as the IBR finger and coordinates its two zinc atoms in a sequential fashion (see <PDB:1WD2>). The RING2 finger contains a conserved Cys residue that is not involved in Zn(2+) 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 enigmatic [4,5,6,7].
Some proteins known to contain a TRIAD supradomain are listed below:
The profile we developed covers the entire TRIAD supradomain.
PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html --------------------------------------------------------------------------------.Last update:
September 2018 / First entry.
PROSITE method (with tools and information) covered by this documentation:
|1||Authors||van der Reijden B.A. Erpelinck-Verschueren C.A.J. Loewenberg B. Jansen J.H.|
|Title||TRIADs: a new class of proteins with a novel cysteine-rich signature.|
|Source||Protein Sci. 8:1557-1561(1999).|
|Title||Diversification and Specialization of Plant RBR Ubiquitin Ligases.|
|Source||PLoS ONE 5:E11579-E11579(2010).|
|3||Authors||Chen P. Zhang X. Zhao T. Li Y. Gai J.|
|Title||Genome-wide identification and characterization of RBR ubiquitin ligase genes in soybean.|
|Source||PLoS ONE 9:E87282-E87282(2014).|
|4||Authors||Spratt D.E. Walden H. Shaw G.S.|
|Title||RBR E3 ubiquitin ligases: new structures, new insights, new questions.|
|Source||Biochem. J. 458:421-437(2014).|
|5||Authors||Capili A.D. Edghill E.L. Wu K. Borden K.L.B.|
|Title||Structure of the C-terminal RING finger from a RING-IBR-RING/TRIAD motif reveals a novel zinc-binding domain distinct from a RING.|
|Source||J. Mol. Biol. 340:1117-1129(2004).|
|6||Authors||Trempe J.-F. Sauve V. Grenier K. Seirafi M. Tang M.Y. Menade M. Al-Abdul-Wahid S. Krett J. Wong K. Kozlov G. Nagar B. Fon E.A. Gehring K.|
|Title||Structure of parkin reveals mechanisms for ubiquitin ligase activation.|
|7||Authors||Dove K.K. Klevit R.E.|
|Title||RING-Between-RING E3 Ligases: Emerging Themes amid the Variations.|
|Source||J. Mol. Biol. 429:3363-3375(2017).|