UniProt functional annotation for Q9BVA6



	UniProt functional annotation for Q9BVA6

UniProt code: Q9BVA6.

Organism: Homo sapiens (Human).

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

Function: Protein that can both mediate the addition of adenosine 5'- monophosphate (AMP) to specific residues of target proteins (AMPylation), and the removal of the same modification from target proteins (de-AMPylation), depending on the context (By similarity). The side chain of Glu-231 determines which of the two opposing activities (AMPylase or de-AMPylase) will take place (By similarity). Acts as a key regulator of the ERN1/IRE1-mediated unfolded protein response (UPR) by mediating AMPylation or de-AMPylation of HSPA5/BiP (PubMed:25601083). In unstressed cells, acts as an adenylyltransferase by mediating AMPylation of HSPA5/BiP at 'Thr-518', thereby inactivating it (By similarity). In response to endoplasmic reticulum stress, acts as a phosphodiesterase by mediating removal of ATP (de-AMPylation) from HSPA5/BiP at 'Thr-518', leading to restore HSPA5/BiP activity (By similarity). Although it is able to AMPylate RhoA, Rac and Cdc42 Rho GTPases in vitro, Rho GTPases do not constitute physiological substrates (PubMed:19362538, PubMed:25601083). {ECO:0000250|UniProtKB:A0A061I403, ECO:0000269|PubMed:22266942, ECO:0000269|PubMed:25435325, ECO:0000269|PubMed:25601083, ECO:0000305|PubMed:19362538}.

Catalytic activity: Reaction=ATP + L-tyrosyl-[protein] = diphosphate + O-(5'-adenylyl)-L- tyrosyl-[protein]; Xref=Rhea:RHEA:54288, Rhea:RHEA-COMP:10136, Rhea:RHEA-COMP:13846, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:46858, ChEBI:CHEBI:83624; EC=2.7.7.n1; Evidence={ECO:0000269|PubMed:19362538};

Catalytic activity: Reaction=3-O-(5'-adenylyl)-L-threonyl-[protein] + H2O = AMP + H(+) + L- threonyl-[protein]; Xref=Rhea:RHEA:55932, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:13847, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:138113, ChEBI:CHEBI:456215; Evidence={ECO:0000250|UniProtKB:A0A061I403};

Catalytic activity: Reaction=ATP + L-threonyl-[protein] = 3-O-(5'-adenylyl)-L-threonyl- [protein] + diphosphate; Xref=Rhea:RHEA:54292, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:13847, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:138113; EC=2.7.7.n1; Evidence={ECO:0000269|PubMed:19362538, ECO:0000269|PubMed:25435325, ECO:0000269|PubMed:25601083};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:25601083}; Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000269|PubMed:25601083}; Note=Divalent metal cation. Prefers Mn(2+) over Mg(2+). {ECO:0000269|PubMed:25601083};

Activity regulation: The side chain of Glu-234 determines which of the two opposing activities (AMPylase or de-AMPylase) will take place. In response to endoplasmic reticulum stress, mediates de-AMPylase activity (By similarity). Adenylyltransferase activity is inhibited by the inhibitory helix present at the N-terminus: Glu-234 binds ATP and competes with ATP-binding at Arg-374, thereby preventing adenylyltransferase activity (PubMed:22266942, PubMed:25435325). In unstressed cells, disengagement of Glu-234 promotes adenylyltransferase activity (By similarity). Activation dissociates ATP-binding from Glu- 234, allowing ordered binding of the entire ATP moiety with the alpha- phosphate in an orientation that is productive for accepting an incoming target hydroxyl side chain (PubMed:22266942, PubMed:25435325). {ECO:0000250|UniProtKB:A0A061I403, ECO:0000269|PubMed:22266942, ECO:0000269|PubMed:25435325}.

Subunit: Homodimer (PubMed:25435325). Interacts with HD (PubMed:9700202). {ECO:0000269|PubMed:25435325, ECO:0000269|PubMed:9700202}.

Subcellular location: Endoplasmic reticulum membrane {ECO:0000269|PubMed:25601083}; Single-pass type II membrane protein {ECO:0000305|PubMed:25601083}.

Tissue specificity: Ubiquitous. {ECO:0000269|PubMed:19362538}.

Induction: Up-regulated in response to activation of unfolded protein response (UPR). {ECO:0000269|PubMed:25601083}.

Domain: The fido domain mediates the adenylyltransferase activity. {ECO:0000269|PubMed:19362538}.

Ptm: Auto-AMPylated in vitro; it is unclear whether auto-AMPylation is relevant in vivo. {ECO:0000269|PubMed:25435325, ECO:0000269|PubMed:25601083}.

Ptm: N-glycosylated; predominantly glycosylated at Asn-275. {ECO:0000269|PubMed:25601083}.

Similarity: Belongs to the fic family. {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:		Protein that can both mediate the addition of adenosine 5'- monophosphate (AMP) to specific residues of target proteins (AMPylation), and the removal of the same modification from target proteins (de-AMPylation), depending on the context (By similarity). The side chain of Glu-231 determines which of the two opposing activities (AMPylase or de-AMPylase) will take place (By similarity). Acts as a key regulator of the ERN1/IRE1-mediated unfolded protein response (UPR) by mediating AMPylation or de-AMPylation of HSPA5/BiP (PubMed:25601083). In unstressed cells, acts as an adenylyltransferase by mediating AMPylation of HSPA5/BiP at 'Thr-518', thereby inactivating it (By similarity). In response to endoplasmic reticulum stress, acts as a phosphodiesterase by mediating removal of ATP (de-AMPylation) from HSPA5/BiP at 'Thr-518', leading to restore HSPA5/BiP activity (By similarity). Although it is able to AMPylate RhoA, Rac and Cdc42 Rho GTPases in vitro, Rho GTPases do not constitute physiological substrates (PubMed:19362538, PubMed:25601083). {ECO:0000250\|UniProtKB:A0A061I403, ECO:0000269\|PubMed:22266942, ECO:0000269\|PubMed:25435325, ECO:0000269\|PubMed:25601083, ECO:0000305\|PubMed:19362538}.


Catalytic activity:		Reaction=ATP + L-tyrosyl-[protein] = diphosphate + O-(5'-adenylyl)-L- tyrosyl-[protein]; Xref=Rhea:RHEA:54288, Rhea:RHEA-COMP:10136, Rhea:RHEA-COMP:13846, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:46858, ChEBI:CHEBI:83624; EC=2.7.7.n1; Evidence={ECO:0000269\|PubMed:19362538};
Catalytic activity:		Reaction=3-O-(5'-adenylyl)-L-threonyl-[protein] + H2O = AMP + H(+) + L- threonyl-[protein]; Xref=Rhea:RHEA:55932, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:13847, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:138113, ChEBI:CHEBI:456215; Evidence={ECO:0000250\|UniProtKB:A0A061I403};
Catalytic activity:		Reaction=ATP + L-threonyl-[protein] = 3-O-(5'-adenylyl)-L-threonyl- [protein] + diphosphate; Xref=Rhea:RHEA:54292, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:13847, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:138113; EC=2.7.7.n1; Evidence={ECO:0000269\|PubMed:19362538, ECO:0000269\|PubMed:25435325, ECO:0000269\|PubMed:25601083};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:25601083}; Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000269\|PubMed:25601083}; Note=Divalent metal cation. Prefers Mn(2+) over Mg(2+). {ECO:0000269\|PubMed:25601083};
Activity regulation:		The side chain of Glu-234 determines which of the two opposing activities (AMPylase or de-AMPylase) will take place. In response to endoplasmic reticulum stress, mediates de-AMPylase activity (By similarity). Adenylyltransferase activity is inhibited by the inhibitory helix present at the N-terminus: Glu-234 binds ATP and competes with ATP-binding at Arg-374, thereby preventing adenylyltransferase activity (PubMed:22266942, PubMed:25435325). In unstressed cells, disengagement of Glu-234 promotes adenylyltransferase activity (By similarity). Activation dissociates ATP-binding from Glu- 234, allowing ordered binding of the entire ATP moiety with the alpha- phosphate in an orientation that is productive for accepting an incoming target hydroxyl side chain (PubMed:22266942, PubMed:25435325). {ECO:0000250\|UniProtKB:A0A061I403, ECO:0000269\|PubMed:22266942, ECO:0000269\|PubMed:25435325}.
Subunit:		Homodimer (PubMed:25435325). Interacts with HD (PubMed:9700202). {ECO:0000269\|PubMed:25435325, ECO:0000269\|PubMed:9700202}.
Subcellular location:		Endoplasmic reticulum membrane {ECO:0000269\|PubMed:25601083}; Single-pass type II membrane protein {ECO:0000305\|PubMed:25601083}.
Tissue specificity:		Ubiquitous. {ECO:0000269\|PubMed:19362538}.
Induction:		Up-regulated in response to activation of unfolded protein response (UPR). {ECO:0000269\|PubMed:25601083}.
Domain:		The fido domain mediates the adenylyltransferase activity. {ECO:0000269\|PubMed:19362538}.
Ptm:		Auto-AMPylated in vitro; it is unclear whether auto-AMPylation is relevant in vivo. {ECO:0000269\|PubMed:25435325, ECO:0000269\|PubMed:25601083}.
Ptm:		N-glycosylated; predominantly glycosylated at Asn-275. {ECO:0000269\|PubMed:25601083}.
Similarity:		Belongs to the fic family. {ECO:0000305}.