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:
- 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.
- Parkin, implicated in a range of biological processes, including autophagy
of damaged mitochondria (mitophagy), cell survival pathways, and vesicle
trafficking. Mutations in the prakin gene are responsible for an autosomal
recessive of Parkinson's disease, a common neurodegenerative disease
characterized by severe motor and nonmotor symptoms.
- Two linear uniquitin chain assembly complex (LUBAC) proteins, heme-oxidized
IRP2 ubiquitin ligase 1L (HOIL-1L) and HOIL-1L interacting protein (HOIP).
The LUBAC complex is associated with B-cell function, regulation of
apoptosis, oncogenesis, and diverse autoimmune diseases.
The profile we developed covers the entire TRIAD supradomain.
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