ADP-ribosylation of arginine

Abstract

Arginine adenosine-5′-diphosphoribosylation (ADP-ribosylation) is an enzyme-catalyzed, potentially reversible posttranslational modification, in which the ADP-ribose moiety is transferred from NAD+ to the guanidino moiety of arginine. At 540 Da, ADP-ribose has the size of approximately five amino acid residues. In contrast to arginine, which, at neutral pH, is positively charged, ADP-ribose carries two negatively charged phosphate moieties. Arginine ADP-ribosylation, thus, causes a notable change in size and chemical property at the ADP-ribosylation site of the target protein. Often, this causes steric interference of the interaction of the target protein with binding partners, e.g. toxin-catalyzed ADP-ribosylation of actin at R177 sterically blocks actin polymerization. In case of the nucleotide-gated P2X7 ion channel, ADP-ribosylation at R125 in the vicinity of the ligand-binding site causes channel gating. Arginine-specific ADP-ribosyltransferases (ARTs) carry a characteristic R-S-EXE motif that distinguishes these enzymes from structurally related enzymes which catalyze ADP-ribosylation of other amino acid side chains, DNA, or small molecules. Arginine-specific ADP-ribosylation can be inhibited by small molecule arginine analogues such as agmatine or meta-iodobenzylguanidine (MIBG), which themselves can serve as targets for arginine-specific ARTs. ADP-ribosylarginine specific hydrolases (ARHs) can restore target protein function by hydrolytic removal of the entire ADP-ribose moiety. In some cases, ADP-ribosylarginine is processed into secondary posttranslational modifications, e.g. phosphoribosylarginine or ornithine. This review summarizes current knowledge on arginine-specific ADP-ribosylation, focussing on the methods available for its detection, its biological consequences, and the enzymes responsible for this modification and its reversal, and discusses future perspectives for research in this field.

Aryl Hydrocarbon Receptor Activation by Dioxin Targets Phosphoenolpyruvate Carboxykinase (PEPCK) for ADP-ribosylation via 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-inducible Poly(ADP-ribose) Polymerase (TiPARP)

“…The effects of ADP-ribosylation on PEPCK activity and stability will merit investigation as ADP-ribosylation has been reported to affect both protein activity and stability (44). For example, ADP-ribosylation enhances transcriptional activation by histones (45) and increases activity of the cation channel P2X7 (44,46) and of the transcriptional insulator CCCTCbinding factor (47) and decreases activity of glutamate dehydrogenase (48), glycogen synthase kinase 3␤ (49), and the circadian rhythm regulator CLOCK (50).…”

“…For example, ADP-ribosylation enhances transcriptional activation by histones (45) and increases activity of the cation channel P2X7 (44,46) and of the transcriptional insulator CCCTCbinding factor (47) and decreases activity of glutamate dehydrogenase (48), glycogen synthase kinase 3␤ (49), and the circadian rhythm regulator CLOCK (50). ADP-ribosylation has also been reported to enhance protein ubiquitination and degradation (51,52).…”

Identification of novel components of NAD-utilizing metabolic pathways and prediction of their biochemical functions

“…7,14 It achieves this by virtue of the facile transition of the nicotinamide ring between hydrogenated and dehydrogenated states. As a substrate in protein and nucleic acid modification it supplies the ADP-ribose moiety for modification of side chains of amino acids such as glutamate, glutamine, lysine, asparagine, cysteine and diphthamide (a modified histidine) and arginine and guanine in DNA [15][16][17][18][19][20] ( Fig. 1).…”

“…4). [16][17][18][19][20][21]31,47 Comparison of the multiple alignment of this family with those of other members of the ART superfamily revealed an HxT signature in the first strand, a conserved Y in the second strand and a QxE signature in the 5th strand. These positions correspond to the key catalytic motifs of the superfamily that tightly envelop the NAD in the active site.…”

“…These positions correspond to the key catalytic motifs of the superfamily that tightly envelop the NAD in the active site. [16][17][18][19][20][21]31,47 The presence of the acidic residue in the 5th strand (i.e. the E) and a large insert between the 4th and 5th strands and the absence of a N-terminal winged HTH domain distinguish the classical ARTs which modify proteins and bases from the KptA-like enzymes, which act on 2 0 -phosphates.…”