Abstract
Arginine-specific mono-adenosine diphosphate (ADP)-ribosylation is a nicotinamide adenine dinucleotide (NAD)+-dependent, reversible post-translational modification involving the transfer of an ADP-ribose from NAD+ by bacterial toxins and eukaryotic ADP-ribosyltransferases (ARTs) to arginine on an acceptor protein or peptide. ADP-ribosylarginine hydrolase 1 (ARH1) catalyzes the cleavage of the ADP-ribose-arginine bond, regenerating (arginine)protein. Arginine-specific mono-ADP-ribosylation catalyzed by bacterial toxins was first identified as a mechanism of disease pathogenesis. Cholera toxin ADP-ribosylates and activates the α subunit of Gαs, a guanine nucleotide-binding protein that stimulates adenylyl cyclase activity, increasing cyclic adenosine monophosphate (cAMP), and resulting in fluid and electrolyte loss. Arginine-specific mono-ADP-ribosylation in mammalian cells has potential roles in membrane repair, immunity, and cancer. In mammalian tissues, ARH1 is a cytosolic protein that is ubiquitously expressed. ARH1 deficiency increased tumorigenesis in a gender-specific manner. In the myocardium, in response to cellular injury, an arginine-specific mono-ADP-ribosylation cycle, involving ART1 and ARH1, regulated the level and cellular distribution of ADP-ribosylated tripartite motif-containing protein 72 (TRIM72). Confirmed substrates of ARH1 in vivo are Gαs and TRIM72, however, more than a thousand proteins, ADP-ribosylated on arginine, have been identified by proteomic analysis. This review summarizes the current understanding of the properties of ARH1, e.g., bacterial toxin action, myocardial membrane repair following injury, and tumorigenesis.
Highlights
Arginine-specific mono-adenosine diphosphate (ADP)-ribosylation is a nicotinamide adenine dinucleotide (NAD)+ -dependent, reversible post-translational modification involving the transfer of an ADP-ribose from NAD+ by bacterial toxins and eukaryotic ADP-ribosyltransferases (ARTs) to arginine on an acceptor protein or peptide
Arginine-specific ADP-ribosyltransferase activity in mouse heart did not differ between wild-type and Arh1-deficient mice, suggesting that the accumulation of ADP-ribosylarginine content is due to ADP-ribosylarginine hydrolase 1 (ARH1) deficiency in Arh1−/− mice [27]
The amount of ADP-ribosyl Gαs in the presence of cholera toxin was greater in Arh1-deficient mice, which suggests that, in wild-type mice, ARH1 cleaves ADP-ribose from Gαs, thereby generating unmodified Gαs and reducing fluid accumulation caused by cholera toxin [26]
Summary
ADP-ribosylarginine hydrolase 1 (ARH1) is a member of an ADP-ribosyl-acceptor hydrolase (ARH) family, which is composed of three 39-kDa proteins, ARH1-3, based on sequence and size similarity. These hydrolases differ in enzymatic activities and biological functions [1]. The active sites of ARH1 (human, mouse, or rat) contain aspartates residues for coordination of Mg2+ binding [5,6]. Critical residues involved in ARH1 enzymatic activity and binding of ADP-ribose include the conserved vicinal aspartates 55 and 56 in humans [5,6] and 60 and 61 in rats [7]. Asp and/or Asp in rats with alanine, glutamine, or asparagine significantly reduced hydrolase activity (ADP-ribosylarginine hydrolase, α-NADase) [5,6,7]
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