The UBR-type zinc finger forms a pocket that mediates recognition of type 1 N-degrons (PubMed:38030679). It can also recognize type-2 N-degrons via two phenylalanines, Phe-1671 and Phe-1713, on its hydrophobic surface (PubMed:38030679). In addition to substrate-binding, the UBR-type zinc finger probably positions substrate proteins in the proximity of the bound and activated E2-ubiquitin conjugate to enable their ubiquitination (PubMed:38182926).
Constitutes an atypical E3 ubiquitin-protein ligase composed of a hemiRING-type zinc finger, a UBR-type zinc-finger interacting subdomain (UZI) and an N-terminal region that can serve as an affinity factor for the E2 conjugating enzymes UBE2A and UBE2B (PubMed:38182926). Compared to classical RING-type, the hemiRING-type only binds a single zinc ion: a hydrogen bonding network is present instead of a second zinc ion (PubMed:38182926). The hemiRING-type zinc finger maintains specificity for E2 conjugating enzymes UBE2A and UBE2B, which have high intrinsic lysine reactivity, obviating the need for the robust thioester activation of classical RING-type E3 ubiquitin-protein ligases (PubMed:38182926).
E3 ubiquitin-protein ligase involved in different protein quality control pathways in the cytoplasm (PubMed:25582440, PubMed:29033132, PubMed:34893540, PubMed:37891180, PubMed:38030679, PubMed:38182926, PubMed:38297121). Component of the N-end rule pathway: ubiquitinates proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their degradation (PubMed:34893540, PubMed:37891180, PubMed:38030679). Recognizes both type-1 and type-2 N-degrons, containing positively charged amino acids (Arg, Lys and His) and bulky and hydrophobic amino acids, respectively (PubMed:38030679). Does not ubiquitinate proteins that are acetylated at the N-terminus (PubMed:37891180). Together with UBR5, part of a cytoplasm protein quality control pathway that prevents protein aggregation by catalyzing assembly of heterotypic 'Lys-11'-/'Lys-48'-linked branched ubiquitin chains on aggregated proteins, leading to substrate recognition by the segregase p97/VCP and degradation by the proteasome: UBR4 probably synthesizes mixed chains containing multiple linkages, while UBR5 is likely branching multiple 'Lys-48'-linked chains of substrates initially modified (PubMed:29033132). Together with KCMF1, part of a protein quality control pathway that catalyzes ubiquitination and degradation of proteins that have been oxidized in response to reactive oxygen species (ROS): recognizes proteins with an Arg-CysO3(H) degron at the N-terminus, and mediates assembly of heterotypic 'Lys-63'-/'Lys-27'-linked branched ubiquitin chains on oxidized proteins, leading to their degradation by autophagy (PubMed:34893540). Catalytic component of the SIFI complex, a multiprotein complex required to inhibit the mitochondrial stress response after a specific stress event has been resolved: ubiquitinates and degrades (1) components of the HRI-mediated signaling of the integrated stress response, such as DELE1 and EIF2AK1/HRI, as well as (2) unimported mitochondrial precursors (PubMed:38297121). Within the SIFI complex, UBR4 initiates ubiquitin chain that are further elongated or branched by KCMF1 (PubMed:38297121). Mediates ubiquitination of ACLY, leading to its subsequent degradation (PubMed:23932781). Together with clathrin, forms meshwork structures involved in membrane morphogenesis and cytoskeletal organization (PubMed:16214886).
Episodic ataxia 8
EA8
A form of episodic ataxia, a neurologic disorder characterized by episodes of poor coordination and balance. EA8 affected individuals have attacks of unsteadiness, general weakness, and slurred speech. Additional variable features include twitching around the eyes, nystagmus, myokymia, and persistent intention tremor. Inheritance is autosomal dominant.
None
The gene represented in this entry may be involved in disease pathogenesis.
Protein modification; protein ubiquitination.
Belongs to the UBR4 family.
KIAA0462, KIAA1307, RBAF600, ZUBR1, UBR4, E3 ubiquitin-protein ligase UBR4, 600 kDa retinoblastoma protein-associated factor, N-recognin-4, Retinoblastoma-associated factor of 600 kDa, p600
Proteins
Epigenetics
573841Da
We found 5 products in 2 categories
ab86738
ab114109