7l9h
From Proteopedia
Crystal structure of human ARH3-D77A bound to magnesium and ADP-ribose
Structural highlights
DiseaseADPRS_HUMAN The disease is caused by variants affecting the gene represented in this entry. FunctionADPRS_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 PubMedADP-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. Loading citation details.. Citations No citations found See AlsoReferences
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