PROSITE documentation PDOC52043

UBR4 E3 catalytic module profile

Covalent attachment of the small protein ubiquitin (Ub), typically to lysine residues in protein substrates, regulates a host of cellular processes and is catalyzed by E3 ligases (E3s). Fundamental arms of the Ub system are the N-degron and C-degron pathways, which control proteasomal or autophagic substrate degradation based on the identity of their N- or C-terminal amino acid. The regulated degradation of substrates by the N-/C-degron pathways affects multiple cellular processes, including the elimination of misfolded or mislocalized proteins, maintenance of protein complex stoichiometry, DNA repair, apoptosis, metabolite sensing and neurodevelopment. N-degrons are recognized by an ~70 residue zinc-finger domain known as the UBR box (see <PDOC51157>). Eukaryotic Ubiquitin Protein Ligase E3 Component N-Recognin 4 (UBR4) belongs to the UBR box protein family of E3 ubiquitin ligases, or N-recognins, that functions in the N-end rule degradation pathway. The N-end rule pathway selectively ubiquitinates substrate proteins based on the presence of specific destabilizing residues, or N-degrons, in their N-termini. UBR4 are large multidomain proteins. The catalytic module that carries out ubiquitin (Ub) transfer consists of a 'hemiRING' zinc finger, a helical-rich UBR zinc-finger interacting (UZI) subdomain, and an N-terminal region that can serve as an affinity factor for the E2 conjugating enzyme (E2) [1,2].

The UBR4 E3 module is composed of two apparent domains that constitute a larger fold. The N-terminal hemiRING zinc finger domain has partial structural homology with the canonical cross-brace RING domain and is followed by the second UZI domain containing 11 α-helices that run to the C-terminus (see <PDB:8B5W>). The hemiRING zinc finger domain fold immediately proximal to zinc ion 1 (referred to as the proximal Zn(2+) site), which engages the E2 enzyme in canonical RING domains, is conserved, together with the tailing helix and core β-sheet. However, residues essential for coordinating the second zinc ion (referred to as the distal Zn(2+) site) are conspicuously absent. Substituting for the second zinc ion are four residues that form hydrogen bonds, and are probably required for stabilizing the cross-brace architecture of the hemiRING zinc finger domain [1].

Some proteins known to contain an UBR4 E3 catalytic module are liste below:

• Mammalian UBR4, an essential protein ubiquitously expressed but highly enriched in the central nervous system. It has several prominent functions in the mammalian brain, including neurogenesis, neuronal migration, neuronal survival and signaling. UBR4 has also been implicated in anoikis, viral transformation and the endosome-lyso-some system [1,2].
• Drosophila Poe, the UBR4 orthologue [3,4].
• Arabidopsis BIG, a regulator of polar auxin transport is necessary to regulate the growth and development. BIG is the only UBR4 homologue in Arabidopsis [5].
• Tomato ROSETTE (RO), the orthologue of UBR4 and BIG [6].

We developed a profile that covers the whole UBR4 E3 catalytic module.