UniProt functional annotation for Q9Y4X5



	UniProt functional annotation for Q9Y4X5

UniProt code: Q9Y4X5.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: E3 ubiquitin-protein ligase, which catalyzes ubiquitination of target proteins together with ubiquitin-conjugating enzyme E2 UBE2L3 (PubMed:15236971, PubMed:21532592, PubMed:24076655, PubMed:27565346, PubMed:23707686). 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). {ECO:0000269|PubMed:14623119, ECO:0000269|PubMed:15236971, ECO:0000269|PubMed:17289916, ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:23707686, ECO:0000269|PubMed:24076655, ECO:0000269|PubMed:25624349, ECO:0000269|PubMed:27565346, ECO:0000269|PubMed:29689197}.

Catalytic activity: Reaction=[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- cysteine + [acceptor protein]-N(6)-ubiquitinyl-L-lysine.; EC=2.3.2.31; Evidence={ECO:0000269|PubMed:15236971, ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:27565346};

Activity regulation: Autoinhibited by the ariadne domain, which masks the second RING-type zinc finger that contains the active site and inhibits the E3 activity (PubMed:23707686). Inhibition is relieved upon binding to neddylated cullin-RING ubiquitin ligase complexes, which activate the E3 ligase activity of ARIH1 (PubMed:24076655, PubMed:27565346). {ECO:0000269|PubMed:23707686, ECO:0000269|PubMed:24076655, ECO:0000269|PubMed:27565346}.

Pathway: Protein modification; protein ubiquitination.

Subunit: Interacts (via the first RING-type zinc finger) with UBE2L3 (PubMed:11278816, PubMed:21532592, PubMed:24076655, PubMed:23707686). Associates with cullin-RING ubiquitin ligase (CRL) complexes containing CUL1, CUL2 and CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL1 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL2 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL4A (PubMed:24076655). {ECO:0000269|PubMed:11278816, ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:23707686, ECO:0000269|PubMed:24076655, ECO:0000269|PubMed:27565346}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:11278816, ECO:0000269|PubMed:21590270, ECO:0000269|PubMed:23059369}. Nucleus {ECO:0000269|PubMed:23059369}. Nucleus, Cajal body {ECO:0000269|PubMed:23059369}. Note=Mainly cytoplasmic (PubMed:11278816). Present in Lewy body (PubMed:21590270). {ECO:0000269|PubMed:11278816, ECO:0000269|PubMed:21590270}.

Tissue specificity: Widely expressed. {ECO:0000269|PubMed:10521492}.

Induction: Up-regulated following DNA damage (PubMed:25624349). {ECO:0000269|PubMed:25624349}.

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). {ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:23707686}.

Domain: The Ariadne domain inhibits activity by masking the second RING-type zinc finger that contains the active site (PubMed:23707686). {ECO:0000269|PubMed:23707686}.

Disease: Note=Defects in ARIH1 have been found in several individuals with thoracic aortic aneurysms and cerebrovascular disease. {ECO:0000269|PubMed:29689197}.

Similarity: Belongs to the RBR family. Ariadne subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		E3 ubiquitin-protein ligase, which catalyzes ubiquitination of target proteins together with ubiquitin-conjugating enzyme E2 UBE2L3 (PubMed:15236971, PubMed:21532592, PubMed:24076655, PubMed:27565346, PubMed:23707686). 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). {ECO:0000269\|PubMed:14623119, ECO:0000269\|PubMed:15236971, ECO:0000269\|PubMed:17289916, ECO:0000269\|PubMed:21532592, ECO:0000269\|PubMed:23707686, ECO:0000269\|PubMed:24076655, ECO:0000269\|PubMed:25624349, ECO:0000269\|PubMed:27565346, ECO:0000269\|PubMed:29689197}.


Catalytic activity:		Reaction=[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- cysteine + [acceptor protein]-N(6)-ubiquitinyl-L-lysine.; EC=2.3.2.31; Evidence={ECO:0000269\|PubMed:15236971, ECO:0000269\|PubMed:21532592, ECO:0000269\|PubMed:27565346};
Activity regulation:		Autoinhibited by the ariadne domain, which masks the second RING-type zinc finger that contains the active site and inhibits the E3 activity (PubMed:23707686). Inhibition is relieved upon binding to neddylated cullin-RING ubiquitin ligase complexes, which activate the E3 ligase activity of ARIH1 (PubMed:24076655, PubMed:27565346). {ECO:0000269\|PubMed:23707686, ECO:0000269\|PubMed:24076655, ECO:0000269\|PubMed:27565346}.
Pathway:		Protein modification; protein ubiquitination.
Subunit:		Interacts (via the first RING-type zinc finger) with UBE2L3 (PubMed:11278816, PubMed:21532592, PubMed:24076655, PubMed:23707686). Associates with cullin-RING ubiquitin ligase (CRL) complexes containing CUL1, CUL2 and CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL1 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL2 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL3 (PubMed:24076655, PubMed:27565346). Interacts with neddylated CUL4A (PubMed:24076655). {ECO:0000269\|PubMed:11278816, ECO:0000269\|PubMed:21532592, ECO:0000269\|PubMed:23707686, ECO:0000269\|PubMed:24076655, ECO:0000269\|PubMed:27565346}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:11278816, ECO:0000269\|PubMed:21590270, ECO:0000269\|PubMed:23059369}. Nucleus {ECO:0000269\|PubMed:23059369}. Nucleus, Cajal body {ECO:0000269\|PubMed:23059369}. Note=Mainly cytoplasmic (PubMed:11278816). Present in Lewy body (PubMed:21590270). {ECO:0000269\|PubMed:11278816, ECO:0000269\|PubMed:21590270}.
Tissue specificity:		Widely expressed. {ECO:0000269\|PubMed:10521492}.
Induction:		Up-regulated following DNA damage (PubMed:25624349). {ECO:0000269\|PubMed:25624349}.
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). {ECO:0000269\|PubMed:21532592, ECO:0000269\|PubMed:23707686}.
Domain:		The Ariadne domain inhibits activity by masking the second RING-type zinc finger that contains the active site (PubMed:23707686). {ECO:0000269\|PubMed:23707686}.
Disease:		Note=Defects in ARIH1 have been found in several individuals with thoracic aortic aneurysms and cerebrovascular disease. {ECO:0000269\|PubMed:29689197}.
Similarity:		Belongs to the RBR family. Ariadne subfamily. {ECO:0000305}.