ARIH1
Domain
Members of the RBR family are atypical E3 ligases. They interact with the E2 conjugating enzyme UBE2L3 and function like HECT-type E3 enzymes: they bind E2s via the first RING-type zinc finger, but require an obligate trans-thiolation step during the ubiquitin transfer, requiring a conserved active site Cys residue in the second RING-type zinc finger (PubMed:21532592, PubMed:23707686). The active site probably forms a thioester intermediate with ubiquitin taken from the active-site cysteine of the E2 before ultimately transferring it to a Lys residue on the substrate (PubMed:21532592, PubMed:23707686).
The Ariadne domain inhibits activity by masking the second RING-type zinc finger that contains the active site (PubMed:23707686).
Function
E3 ubiquitin-protein ligase, which catalyzes ubiquitination of target proteins together with ubiquitin-conjugating enzyme E2 UBE2L3 (PubMed:15236971, PubMed:21532592, PubMed:23707686, PubMed:24076655, PubMed:27565346). Acts as an atypical E3 ubiquitin-protein ligase by working together with cullin-RING ubiquitin ligase (CRL) complexes and initiating ubiquitination of CRL substrates: associates with CRL complexes and specifically mediates addition of the first ubiquitin on CRLs targets (PubMed:27565346). The initial ubiquitin is then elongated by CDC34/UBE2R1 and UBE2R2 (PubMed:27565346). E3 ubiquitin-protein ligase activity is activated upon binding to neddylated cullin-RING ubiquitin ligase complexes (PubMed:24076655, PubMed:27565346). Plays a role in protein translation in response to DNA damage by mediating ubiquitination of EIF4E2, the consequences of EIF4E2 ubiquitination are however unclear (PubMed:25624349). According to a report, EIF4E2 ubiquitination leads to promote EIF4E2 cap-binding and protein translation arrest (PubMed:25624349). According to another report EIF4E2 ubiquitination leads to its subsequent degradation (PubMed:14623119). Acts as the ligase involved in ISGylation of EIF4E2 (PubMed:17289916). In vitro, controls the degradation of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex member SUN2 and may therefore have a role in the formation and localization of the LINC complex, and as a consequence, nuclear subcellular localization and nuclear morphology (PubMed:29689197).
Involvement in disease
Defects in ARIH1 have been found in several individuals with thoracic aortic aneurysms and cerebrovascular disease.
Pathway
Protein modification; protein ubiquitination.
Sequence Similarities
Belongs to the RBR family. Ariadne subfamily.
Tissue Specificity
Widely expressed.
Cellular localization
- Cytoplasm
- Nucleus
- Nucleus
- Cajal body
- Mainly cytoplasmic (PubMed:11278816). Present in Lewy body (PubMed:21590270).
Alternative names
ARI, MOP6, UBCH7BP, HUSSY-27, ARIH1, E3 ubiquitin-protein ligase ARIH1, H7-AP2, HHARI, Monocyte protein 6, Protein ariadne-1 homolog, UbcH7-binding protein, UbcM4-interacting protein, Ubiquitin-conjugating enzyme E2-binding protein 1, MOP-6, ARI-1