| Structural highlights
Disease
ADPRS_HUMAN The disease is caused by variants affecting the gene represented in this entry.
Function
ADPRS_HUMAN 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).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
ADP-ribosylation is a reversible and site-specific post-translational modification that regulates a wide array of cellular signaling pathways. Regulation of ADP-ribosylation is vital for maintaining genomic integrity and uncontrolled accumulation of poly(ADP-ribosyl)ation triggers a poly(ADP-ribose) (PAR)-dependent release of apoptosis-inducing factor from mitochondria, leading to cell death. ADP-ribosyl-acceptor hydrolase 3 (ARH3) cleaves PAR and mono(ADP-ribosyl)ation at serine following DNA damage. ARH3 is also a metalloenzyme with strong metal selectivity. While coordination of two magnesium ions (Mg(A) and Mg(B)) significantly enhances its catalytic efficiency, calcium binding suppresses its function. However, how the coordination of different metal ions affects its catalysis has not been defined. Here we report a new crystal structure of ARH3 complexed with its product ADP-ribose and calcium. This structure shows that calcium coordination significantly distorts the binuclear metal center of ARH3, which results in decreased binding affinity to ADP-ribose, and suboptimal substrate alignment, leading to impaired hydrolysis of PAR and mono(ADP-ribosyl)ated serines. Furthermore, combined structural and mutational analysis of the metal-coordinating acidic residues revealed that Mg(A) is crucial for optimal substrate positioning for catalysis, whereas Mg(B) plays a key role in substrate binding. Our collective data provide novel insights into the different roles of these metal ions and the basis of metal selectivity of ARH3, and contribute to understanding the dynamic regulation of cellular ADP-ribosylations during the DNA damage response.
Structural and biochemical analysis of human ADP-ribosyl-acceptor hydrolase 3 (ARH3) reveals the basis of metal selectivity and different roles for the two Mg ions.,Pourfarjam Y, Ma Z, Kurinov I, Moss J, Kim IK J Biol Chem. 2021 Apr 21:100692. doi: 10.1016/j.jbc.2021.100692. PMID:33894202[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Oka S, Kato J, Moss J. Identification and characterization of a mammalian 39-kDa poly(ADP-ribose) glycohydrolase. J Biol Chem. 2006 Jan 13;281(2):705-13. Epub 2005 Nov 8. PMID:16278211 doi:https://dx.doi.org/M510290200
- ↑ Ono T, Kasamatsu A, Oka S, Moss J. The 39-kDa poly(ADP-ribose) glycohydrolase ARH3 hydrolyzes O-acetyl-ADP-ribose, a product of the Sir2 family of acetyl-histone deacetylases. Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16687-91. doi:, 10.1073/pnas.0607911103. Epub 2006 Oct 30. PMID:17075046 doi:https://dx.doi.org/10.1073/pnas.0607911103
- ↑ Kasamatsu A, Nakao M, Smith BC, Comstock LR, Ono T, Kato J, Denu JM, Moss J. Hydrolysis of O-acetyl-ADP-ribose isomers by ADP-ribosylhydrolase 3. J Biol Chem. 2011 Jun 17;286(24):21110-7. doi: 10.1074/jbc.M111.237636. Epub 2011, Apr 17. PMID:21498885 doi:https://dx.doi.org/10.1074/jbc.M111.237636
- ↑ Niere M, Mashimo M, Agledal L, Dolle C, Kasamatsu A, Kato J, Moss J, Ziegler M. ADP-ribosylhydrolase 3 (ARH3), not poly(ADP-ribose) glycohydrolase (PARG) isoforms, is responsible for degradation of mitochondrial matrix-associated poly(ADP-ribose). J Biol Chem. 2012 May 11;287(20):16088-102. doi: 10.1074/jbc.M112.349183. Epub, 2012 Mar 20. PMID:22433848 doi:https://dx.doi.org/10.1074/jbc.M112.349183
- ↑ Fontana P, Bonfiglio JJ, Palazzo L, Bartlett E, Matic I, Ahel I. Serine ADP-ribosylation reversal by the hydrolase ARH3. Elife. 2017 Jun 26;6. doi: 10.7554/eLife.28533. PMID:28650317 doi:https://dx.doi.org/10.7554/eLife.28533
- ↑ Abplanalp J, Leutert M, Frugier E, Nowak K, Feurer R, Kato J, Kistemaker HVA, Filippov DV, Moss J, Caflisch A, Hottiger MO. Proteomic analyses identify ARH3 as a serine mono-ADP-ribosylhydrolase. Nat Commun. 2017 Dec 12;8(1):2055. doi: 10.1038/s41467-017-02253-1. PMID:29234005 doi:https://dx.doi.org/10.1038/s41467-017-02253-1
- ↑ Palazzo L, Leidecker O, Prokhorova E, Dauben H, Matic I, Ahel I. Serine is the major residue for ADP-ribosylation upon DNA damage. Elife. 2018 Feb 26;7. pii: 34334. doi: 10.7554/eLife.34334. PMID:29480802 doi:https://dx.doi.org/10.7554/eLife.34334
- ↑ Pourfarjam Y, Ventura J, Kurinov I, Cho A, Moss J, Kim IK. Structure of human ADP-ribosyl-acceptor hydrolase 3 bound to ADP-ribose reveals a conformational switch that enables specific substrate recognition. J Biol Chem. 2018 Aug 10;293(32):12350-12359. doi: 10.1074/jbc.RA118.003586. Epub, 2018 Jun 15. PMID:29907568 doi:https://dx.doi.org/10.1074/jbc.RA118.003586
- ↑ Wang M, Yuan Z, Xie R, Ma Y, Liu X, Yu X. Structure-function analyses reveal the mechanism of the ARH3-dependent hydrolysis of ADP-ribosylation. J Biol Chem. 2018 Jul 25. pii: RA118.004284. doi: 10.1074/jbc.RA118.004284. PMID:30045870 doi:https://dx.doi.org/10.1074/jbc.RA118.004284
- ↑ Danhauser K, Alhaddad B, Makowski C, Piekutowska-Abramczuk D, Syrbe S, Gomez-Ospina N, Manning MA, Kostera-Pruszczyk A, Krahn-Peper C, Berutti R, Kovacs-Nagy R, Gusic M, Graf E, Laugwitz L, Roblitz M, Wroblewski A, Hartmann H, Das AM, Bultmann E, Fang F, Xu M, Schatz UA, Karall D, Zellner H, Haberlandt E, Feichtinger RG, Mayr JA, Meitinger T, Prokisch H, Strom TM, Ploski R, Hoffmann GF, Pronicki M, Bonnen PE, Morlot S, Haack TB. Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy. Am J Hum Genet. 2018 Nov 1;103(5):817-825. doi: 10.1016/j.ajhg.2018.10.005. Epub , 2018 Oct 25. PMID:30401461 doi:https://dx.doi.org/10.1016/j.ajhg.2018.10.005
- ↑ Bonfiglio JJ, Leidecker O, Dauben H, Longarini EJ, Colby T, San Segundo-Acosta P, Perez KA, Matic I. An HPF1/PARP1-Based Chemical Biology Strategy for Exploring ADP-Ribosylation. Cell. 2020 Nov 12;183(4):1086-1102.e23. doi: 10.1016/j.cell.2020.09.055. PMID:33186521 doi:https://dx.doi.org/10.1016/j.cell.2020.09.055
- ↑ Pourfarjam Y, Ma Z, Kurinov I, Moss J, Kim IK. Structural and biochemical analysis of human ADP-ribosyl-acceptor hydrolase 3 (ARH3) reveals the basis of metal selectivity and different roles for the two Mg ions. J Biol Chem. 2021 Apr 21:100692. doi: 10.1016/j.jbc.2021.100692. PMID:33894202 doi:https://dx.doi.org/10.1016/j.jbc.2021.100692
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