UniProt functional annotation for Q9NX46



	UniProt functional annotation for Q9NX46

UniProt code: Q9NX46.

Organism: Homo sapiens (Human).

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

Function: ADP-ribose glycohydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1'' position of ADP- ribose and acts on different substrates, such as proteins ADP- ribosylated on serine, free poly(ADP-ribose) and O-acetyl-ADP-D-ribose (PubMed:21498885, PubMed:30045870, PubMed:29907568, PubMed:30401461, PubMed:33186521). Specifically acts as a serine mono-ADP- ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to serine residues on proteins, thereby playing a key role in DNA damage response (PubMed:28650317, PubMed:29234005, PubMed:30045870, PubMed:33186521). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802, PubMed:33186521). Does not hydrolyze ADP-ribosyl- arginine, -cysteine, -diphthamide, or -asparagine bonds (PubMed:16278211). Also able to degrade protein free poly(ADP-ribose), which is synthesized in response to DNA damage: free poly(ADP-ribose) acts as a potent cell death signal and its degradation by ADPRHL2 protects cells from poly(ADP-ribose)-dependent cell death, a process named parthanatos (PubMed:16278211). Also hydrolyzes free poly(ADP- ribose) in mitochondria (PubMed:22433848). Specifically digests O- acetyl-ADP-D-ribose, a product of deacetylation reactions catalyzed by sirtuins (PubMed:17075046, PubMed:21498885). Specifically degrades 1''- O-acetyl-ADP-D-ribose isomer, rather than 2''-O-acetyl-ADP-D-ribose or 3''-O-acetyl-ADP-D-ribose isomers (PubMed:21498885). {ECO:0000269|PubMed:16278211, ECO:0000269|PubMed:17075046, ECO:0000269|PubMed:21498885, ECO:0000269|PubMed:22433848, ECO:0000269|PubMed:28650317, ECO:0000269|PubMed:29234005, ECO:0000269|PubMed:29480802, ECO:0000269|PubMed:29907568, ECO:0000269|PubMed:30045870, ECO:0000269|PubMed:30401461, ECO:0000269|PubMed:33186521}.

Catalytic activity: Reaction=[(1''->2')-ADP-alpha-D-ribose]n + H2O = [(1''->2')-ADP-alpha- D-ribose]n-1 + ADP-D-ribose; Xref=Rhea:RHEA:52216, Rhea:RHEA- COMP:16922, Rhea:RHEA-COMP:16923, ChEBI:CHEBI:15377, ChEBI:CHEBI:57967, ChEBI:CHEBI:142512; EC=3.2.1.143; Evidence={ECO:0000269|PubMed:16278211, ECO:0000269|PubMed:17075046, ECO:0000269|PubMed:22433848}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:52217; Evidence={ECO:0000269|PubMed:16278211, ECO:0000269|PubMed:17075046, ECO:0000269|PubMed:22433848};

Catalytic activity: Reaction=1''-O-acetyl-ADP-alpha-D-ribose + H2O = acetate + ADP-D-ribose + H(+); Xref=Rhea:RHEA:58112, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30089, ChEBI:CHEBI:57967, ChEBI:CHEBI:142511; Evidence={ECO:0000269|PubMed:17075046, ECO:0000269|PubMed:21498885}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58113; Evidence={ECO:0000269|PubMed:17075046, ECO:0000269|PubMed:21498885};

Catalytic activity: Reaction=H2O + O-(ADP-D-ribosyl)-L-seryl-[protein] = ADP-D-ribose + L- seryl-[protein]; Xref=Rhea:RHEA:58256, Rhea:RHEA-COMP:9863, Rhea:RHEA-COMP:15091, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:57967, ChEBI:CHEBI:142556; Evidence={ECO:0000269|PubMed:28650317, ECO:0000269|PubMed:29234005, ECO:0000269|PubMed:33186521}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58257; Evidence={ECO:0000269|PubMed:28650317, ECO:0000269|PubMed:29234005, ECO:0000269|PubMed:33186521};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:16278211, ECO:0000269|PubMed:17075046, ECO:0000269|PubMed:29907568, ECO:0000269|PubMed:30045870}; Note=Binds 2 magnesium ions per subunit. {ECO:0000269|PubMed:16278211, ECO:0000269|PubMed:29907568, ECO:0000269|PubMed:30045870};

Activity regulation: The protein undergoes a dramatic conformational switch from closed to open states upon substrate-binding, which enables specific substrate recognition for the 1''-O-linkage (PubMed:29907568). The glutamate flap (Glu-41) blocks substrate entrance to Mg(2+) in the unliganded closed state (PubMed:30045870, PubMed:29907568). In presence of substrate, Glu-41 is ejected from the active site: this closed-to- open transition significantly widens the substrate-binding channel and precisely positions the scissile 1''-O-linkage for cleavage while securing tightly 2'- and 3'-hydroxyls of ADP-ribose (PubMed:30045870, PubMed:29907568). {ECO:0000269|PubMed:29907568, ECO:0000269|PubMed:30045870}.

Subunit: Monomer. {ECO:0000269|PubMed:17015823}.

Subcellular location: Nucleus {ECO:0000269|PubMed:17991898}. Cytoplasm {ECO:0000269|PubMed:16278211}. Chromosome {ECO:0000269|PubMed:30045870}. Mitochondrion matrix {ECO:0000269|PubMed:17991898, ECO:0000305|PubMed:22433848}. Note=Recruited to DNA lesion regions following DNA damage; ADP-D- ribose-recognition is required for recruitment to DNA damage sites. {ECO:0000269|PubMed:30045870}.

Tissue specificity: Ubiquitous. {ECO:0000269|PubMed:16278211}.

Disease: Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures (CONDSIAS) [MIM:618170]: An autosomal recessive neurodegenerative disorder characterized by pediatric onset of progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. {ECO:0000269|PubMed:30100084, ECO:0000269|PubMed:30401461}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the ADP-ribosylglycohydrolase family. {ECO:0000305}.

Sequence caution: Sequence=AAK14922.1; Type=Frameshift; Evidence={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:		ADP-ribose glycohydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1'' position of ADP- ribose and acts on different substrates, such as proteins ADP- ribosylated on serine, free poly(ADP-ribose) and O-acetyl-ADP-D-ribose (PubMed:21498885, PubMed:30045870, PubMed:29907568, PubMed:30401461, PubMed:33186521). Specifically acts as a serine mono-ADP- ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to serine residues on proteins, thereby playing a key role in DNA damage response (PubMed:28650317, PubMed:29234005, PubMed:30045870, PubMed:33186521). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802, PubMed:33186521). Does not hydrolyze ADP-ribosyl- arginine, -cysteine, -diphthamide, or -asparagine bonds (PubMed:16278211). Also able to degrade protein free poly(ADP-ribose), which is synthesized in response to DNA damage: free poly(ADP-ribose) acts as a potent cell death signal and its degradation by ADPRHL2 protects cells from poly(ADP-ribose)-dependent cell death, a process named parthanatos (PubMed:16278211). Also hydrolyzes free poly(ADP- ribose) in mitochondria (PubMed:22433848). Specifically digests O- acetyl-ADP-D-ribose, a product of deacetylation reactions catalyzed by sirtuins (PubMed:17075046, PubMed:21498885). Specifically degrades 1''- O-acetyl-ADP-D-ribose isomer, rather than 2''-O-acetyl-ADP-D-ribose or 3''-O-acetyl-ADP-D-ribose isomers (PubMed:21498885). {ECO:0000269\|PubMed:16278211, ECO:0000269\|PubMed:17075046, ECO:0000269\|PubMed:21498885, ECO:0000269\|PubMed:22433848, ECO:0000269\|PubMed:28650317, ECO:0000269\|PubMed:29234005, ECO:0000269\|PubMed:29480802, ECO:0000269\|PubMed:29907568, ECO:0000269\|PubMed:30045870, ECO:0000269\|PubMed:30401461, ECO:0000269\|PubMed:33186521}.


Catalytic activity:		Reaction=[(1''->2')-ADP-alpha-D-ribose]n + H2O = [(1''->2')-ADP-alpha- D-ribose]n-1 + ADP-D-ribose; Xref=Rhea:RHEA:52216, Rhea:RHEA- COMP:16922, Rhea:RHEA-COMP:16923, ChEBI:CHEBI:15377, ChEBI:CHEBI:57967, ChEBI:CHEBI:142512; EC=3.2.1.143; Evidence={ECO:0000269\|PubMed:16278211, ECO:0000269\|PubMed:17075046, ECO:0000269\|PubMed:22433848}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:52217; Evidence={ECO:0000269\|PubMed:16278211, ECO:0000269\|PubMed:17075046, ECO:0000269\|PubMed:22433848};
Catalytic activity:		Reaction=1''-O-acetyl-ADP-alpha-D-ribose + H2O = acetate + ADP-D-ribose + H(+); Xref=Rhea:RHEA:58112, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30089, ChEBI:CHEBI:57967, ChEBI:CHEBI:142511; Evidence={ECO:0000269\|PubMed:17075046, ECO:0000269\|PubMed:21498885}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58113; Evidence={ECO:0000269\|PubMed:17075046, ECO:0000269\|PubMed:21498885};
Catalytic activity:		Reaction=H2O + O-(ADP-D-ribosyl)-L-seryl-[protein] = ADP-D-ribose + L- seryl-[protein]; Xref=Rhea:RHEA:58256, Rhea:RHEA-COMP:9863, Rhea:RHEA-COMP:15091, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:57967, ChEBI:CHEBI:142556; Evidence={ECO:0000269\|PubMed:28650317, ECO:0000269\|PubMed:29234005, ECO:0000269\|PubMed:33186521}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58257; Evidence={ECO:0000269\|PubMed:28650317, ECO:0000269\|PubMed:29234005, ECO:0000269\|PubMed:33186521};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:16278211, ECO:0000269\|PubMed:17075046, ECO:0000269\|PubMed:29907568, ECO:0000269\|PubMed:30045870}; Note=Binds 2 magnesium ions per subunit. {ECO:0000269\|PubMed:16278211, ECO:0000269\|PubMed:29907568, ECO:0000269\|PubMed:30045870};
Activity regulation:		The protein undergoes a dramatic conformational switch from closed to open states upon substrate-binding, which enables specific substrate recognition for the 1''-O-linkage (PubMed:29907568). The glutamate flap (Glu-41) blocks substrate entrance to Mg(2+) in the unliganded closed state (PubMed:30045870, PubMed:29907568). In presence of substrate, Glu-41 is ejected from the active site: this closed-to- open transition significantly widens the substrate-binding channel and precisely positions the scissile 1''-O-linkage for cleavage while securing tightly 2'- and 3'-hydroxyls of ADP-ribose (PubMed:30045870, PubMed:29907568). {ECO:0000269\|PubMed:29907568, ECO:0000269\|PubMed:30045870}.
Subunit:		Monomer. {ECO:0000269\|PubMed:17015823}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:17991898}. Cytoplasm {ECO:0000269\|PubMed:16278211}. Chromosome {ECO:0000269\|PubMed:30045870}. Mitochondrion matrix {ECO:0000269\|PubMed:17991898, ECO:0000305\|PubMed:22433848}. Note=Recruited to DNA lesion regions following DNA damage; ADP-D- ribose-recognition is required for recruitment to DNA damage sites. {ECO:0000269\|PubMed:30045870}.
Tissue specificity:		Ubiquitous. {ECO:0000269\|PubMed:16278211}.
Disease:		Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures (CONDSIAS) [MIM:618170]: An autosomal recessive neurodegenerative disorder characterized by pediatric onset of progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. {ECO:0000269\|PubMed:30100084, ECO:0000269\|PubMed:30401461}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the ADP-ribosylglycohydrolase family. {ECO:0000305}.
Sequence caution:		Sequence=AAK14922.1; Type=Frameshift; Evidence={ECO:0000305};