ADP-ribose glycohydrolase ARH3 (ADPRHL2)
The protein contains 363 amino acids for an estimated molecular weight of 38947 Da.
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 (updated: April 7, 2021)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| dbSNP:rs2236387 | |
| CONDSIAS | |
| CONDSIAS | |
| CONDSIAS | |
| CONDSIAS |
No binding partner found
Biological Process
Base-excision repair, gap-filling
Cellular response to superoxide
DNA repair
Peptidyl-serine ADP-deribosylation
Cellular Component
Mitochondrial matrix
Mitochondrion
Nuclear body
Nucleoplasm
Nucleus
Site of DNA damage
The reference OMIM entry for this protein is 610624
Adp-ribosylhydrolase-like 2; adprhl2
Adp-ribosylhydrolase 3; arh3
DESCRIPTION
ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases (see ART1; 601625) transfer ADP-ribose from NAD+ to the target protein, and ADP-ribosylhydrolases, such as ADPRHL2, reverse the reaction (Glowacki et al., 2002).CLONING
By database analysis and PCR of brain cDNA libraries, Oka et al. (2006) cloned mouse and human ADPRHL2, which they called ARH3. The deduced human protein contains 363 amino acids and is 92% identical to its mouse homolog. Northern blot analysis of mouse tissues showed ubiquitous expression of Arh3. Western blot analysis of a human liver carcinoma cell line detected ARH3 in the cytosolic fraction, but not in nuclei. Analysis of mouse brain and liver revealed Arh3 in both the cytosolic and nuclear fractions.BIOCHEMICAL FEATURES
Mueller-Dieckmann et al. (2006) determined the crystal structure of ARH3 lacking its N-terminal 16 amino acids in the presence and absence of ADP to 1.6 angstrom resolution. They found that ARH3 assumes an all-alpha-helical fold, and that 2 magnesium ions are flanked by highly conserved amino acids in the active-site crevice.GENE FUNCTION
Oka et al. (2006) found that mouse and human ARH3 degraded poly(ADP-ribose) covalently linked to PARP (173870), but they were unable to hydrolyze ADP-ribose-arginine, -cysteine, -diphthamide, or -asparagine bonds. ARH3 activity was enhanced by MgCl(2+). Mutation of asp77 and asp78 of ARH3 eliminated ribosylhydrolase activity, but not binding to ADP ribose. Mueller-Dieckmann et al. (2006) found that human ARH3 bound free ADP-ribose with micromolar affinity and efficiently de-ADP-ribosylated poly- but not mono-ADP-ribosylated proteins. Binding, docking, and mutagenesis experiments suggested a mode of substrate binding and a reaction mechanism involving Mg(2+) and critical aspartic acid residues.MAPPING
By genomic sequence analysis, Glowacki et al. (2002) mapped the ADPRH2 gene to chromosome 1p35.3-p34.1. ... More on the omim web site
April 10, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 22, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Jan. 21, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 610624 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed