Insights into the biogenesis, function, and regulation of ADP-ribosylation

Abstract

ADP-ribosylation—the transfer of ADP-ribose (ADPr) from NAD+ onto target molecules—is catalyzed by members of the ADP-ribosyltransferase (ART) superfamily of proteins, found in all kingdoms of life. Modification of amino acids in protein targets by ADPr regulates critical cellular pathways in eukaryotes and underlies the pathogenicity of certain bacteria. Several members of the ART superfamily are highly relevant for disease; these include the poly(ADP-ribose) polymerases (PARPs), recently shown to be important cancer targets, and the bacterial toxins diphtheria toxin and cholera toxin, long known to be responsible for the symptoms of diphtheria and cholera that result in morbidity. In this Review, we discuss the functions of amino acid ADPr modifications and the ART proteins that make them, the nature of the chemical linkage between ADPr and its targets and how this impacts function and stability, and the way that ARTs select specific amino acids in targets to modify.

Bifunctional Immunity Proteins Protect Bacteria against FtsZ-Targeting ADP-Ribosylating Toxins

“…In all cases, the uncharacterized domain resides at the C-terminus of the protein – the stereotyped position in each of these systems for the toxin domain of their substrates. Subsequent sequence analyses showed that the domain possesses a constellation of conserved amino acids characteristic of RSE family ART enzymes (Figure 1B) (Cohen and Chang, 2018). Bacterial members of this family include eukaryotic cell-targeting toxins; however, members of this family are not known to act between bacterial cells.…”

“…ADP-ribosylation can be a reversible modification, and enzymes belonging to the ARH family are known to catalyze ADP-ribose removal (Cohen and Chang, 2018). Interestingly, we noted that the genes immediately downstream of predicted antibacterial RSE family genes encode ARH family proteins (Figure 1C and Table S1).…”

“…The structure revealed that Tre1 shares a high degree of similarly to the catalytic domains of RSE-type ART enzymes (Figure 3C) (Cohen and Chang, 2018). Among this large and diverse group of proteins found in both bacteria and eukaryotes, Tre1 is most similar to a subset of those which ADP-ribosylate arginine residues, iota toxin from C. perfringens (2.1 Å r.m.s.d., 148 residues) (Tsuge et al, 2003).…”

“…This analysis identified nine ADP-ribosylated (ADPr) peptides deriving from seven proteins in Tre1 tox samples; no ADPr peptides were detected in control E. coli lysates containing Tre1 tox E415Q (Figures 4A and S3A–I). Our search considered all previously identified amino acid targets of ART enzymes (Cys, Gln, Arg, Asn, Thr, Glu, Asp, Lys) (Cohen and Chang, 2018); however, we detected exclusively ADP-ribose–Arg as the product of Tre1 tox . This finding is consistent with the amino acid targeting specificity of the RSE family ART enzymes most structurally related to Tre1(Fu et al, 2007).…”

Emissive Synthetic Cofactors: A Highly Responsive NAD+Analogue Reveals Biomolecular Recognition Features

“…The most prominent role of nicotinamide adenine dinucleotide ( NAD + , Figure ) is as a redox cofactor in regulating central metabolic pathways by catalyzing a variety of oxidoreductase‐mediated processes . Moreover, NAD + has been recently found to act as a substrate for multiple enzymes that catalyze glycosidic cleavage of the nicotinamide moiety and release an ADP‐ribose ( ADPr ) moiety, which is then transferred onto acceptor molecules, such as proteins, DNA, and smaller metabolites …”