This superfamily can be found in two different types of proteins, RNA polymerase II elongation factor ELL and E3 ubiquitin protein ligases UBR1 and UBR2. ELL functions as an E3 ubiquitin ligase and targets c-Myc for proteasomal degradation [].
This entry represents a group of E3 ubiquitin-protein ligases, including UBR1, UBR2 and UBR3. They are part of the N-end rule pathway []. They recognize and bind to proteins bearing specific N-terminal residues, leading to their ubiquitination and subsequent degradation [, ].The UBR1 protein was shown to bind specifically to proteins bearing N-terminalresidues that are destabilising according to the N-end rule, but not tootherwise identical proteins bearing stabilising N-terminal residues []. UBR1 contains an N-terminal conserved region (the UBR-type zinc finger) which is also found in various proteins implicated in N-degron recognition [].
It has been observed that the identity of N-terminal residues of a protein isrelated to the half life of the protein. This observation yields a rule,called the N-end rule []. Similar but distinct versions of the N-end rule operate in all organisms examined, from mammals to fungi and bacteria. Ineukaryotes, the N-end rule pathway is a part of the ubiquitin degradationsystem. Some proteins that have a very short half life contain a specificmotif at their N terminus, the N-degron. It consists of a destabilisingN-terminal residue and an internal Lys, which is the site of poly-Ub chain[, ].The UBR1 protein was shown to bind specifically to proteins bearing N-terminalresidues that are destabilising according to the N-end rule, but not tootherwise identical proteins bearing stabilising N-terminal residues []. UBR1 contains an N-terminal conserved region (the UBR-type zinc finger) which is also found in various proteins implicated in N-degron recognition. The UBR-type zinc finger defines a unique E3 class, most likely N-degron specific [].
UBR box family is a unique class of E3 ligases that recognise N-degrons or structurally related determinants for ubiquitin-dependent proteolysis. They belong to the N-end rule pathway which relates the identity of the N-terminal residue of a protein with its half-life, recognising destabilising ones. Some of the functions of this pathway include the control of peptide import, the fidelity of chromosome segregation, the regulation of apoptosis, as well as regulation of meiosis in yeasts and metazoans, leaf senescence in plants, and cardiovascular development in mammals []. These proteins contain an N-terminal UBR box (a substrate-binding domain), which is highly conserved among UBR family members, a cysteine- and histidine-rich RING (RING-H2) domain, which is present in a larger class of E3 ubiquitin ligases and some additional domains that vary among UBR family members, like these described in UBR1 []: ClpS, a region of sequence similarity to prokaryotic ClpS which acts as an accessory subunit that contributes to recognition of degrons by the ATP-dependent protease ClpAP, a BRR (basic residue-rich region), a conserved motif that contributes to the binding of yeast UBR1 to the E2 enzyme RAD6, and conserved regions [, , ].This entry represents the C-terminal domain which includes a conserved region found in E3 ubiquitin-protein ligase UBR1, 2, 3 from animals, UBR1/11 from fission yeast, and also in PRT6 from Arabidopsis thaliana [].
This entry includes fission yeast tethering factor for nuclear proteasome Cut8 protein and its homologue, Sts1. In Schizosaccharomyces pombe, Cut8 is a nuclear envelope protein that physically interacts with and tethers 26S proteasome in the nucleus resulting in the nuclear accumulation of proteasome []. Cut8 comprises three functional domains. An N-terminal lysine-rich segment which binds to the proteasome when ubiquitinated, a central dimerisation domain and a C-terminal nine-helix, , bundle which shows structural similarity to 14-3-3 phosphoprotein-binding domains. The helical bundle is necessary for liposome and cholesterol binding []. Cut8 is a proteasome substrate and the N-terminal segment is polyubiquitinated and functions as a degron tag. Ubiquitination of the amino N-terminal segment is essential for the function of Cut8 []. Lysine residues in the N-terminal segment of Cut8 are required for physical interaction with proteasome []. In fission yeast the function of Cut8 has been demonstrated to be regulated by ubiquitin-conjugating Rhp6/Ubc2/Rad6 and ligating enzymes Ubr1 []. Cut8 homologues have been identified in Drosophila melanogaster, Anopheles gambiae and Dictyostelium discoideum [].
This entry includes fission yeast Cut8 protein and its homologue, Sts1. In Schizosaccharomyces pombe, Cut8 is a nuclear envelope protein that physically interacts with and tethers 26S proteasome in the nucleus resulting in the nuclear accumulation of proteasome []. Cut8 comprises three functional domains. An N-terminal lysine-rich segment which binds to the proteasome when ubiquitinated, a central dimerisation domain and a C-terminal nine-helix, , bundle which shows structural similarity to 14-3-3 phosphoprotein-binding domains. The helical bundle is necessary for liposome and cholesterol binding []. Cut8 is a proteasome substrate and the N-terminal segment is polyubiquitinated and functions as a degron tag. Ubiquitination of the amino N-terminal segment is essential for the function of Cut8 []. Lysine residues in the N-terminal segment of Cut8 are required for physical interaction with proteasome []. In fission yeast the function of Cut8 has been demonstrated to be regulated by ubiquitin-conjugating Rhp6/Ubc2/Rad6 and ligating enzymes Ubr1 []. Cut8 homologues have been identified in Drosophila melanogaster, Anopheles gambiae and Dictyostelium discoideum [].
