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ADP-ribosylation is a reversible post-translational modification in which one (mono-ADP-ribosylation) or multiple (poly-ADP-ribosylation) ADP-ribose moieties are attached onto a substrate protein by ADP ribosyltransferases.

mono-ADP-Ribosylation

Overview

mono-ADP-ribosylation is a common post-translational modification, where an ADP-ribose moiety is transferred from NAD⁺ to the substrate protein under the release of nicotinamide. The transfer of ADP-ribose occurs onto amino acid residues with a nucleophilic oxygen, nitrogen or sulfur.

In-depth mechanism

mono-ADP-ribosylation describes the process of attaching an ADP-ribose moiety directly onto an amino acid residue with nucleophilic oxygen, nitrogen or sulfur, forming an N-, O- or S-glycosidic bond. The donor of the ADP-moiety is nicotinamide adenine dinucleotide. The transfer is catalysed by various ADP-ribosyltransferasen. During the transfer, nicotinamide is released^​1–6​. Primarily, arginine ^​1–6​, glutamate^​1–5​ and aspartate^​1–5​, but to a lesser extent also asparagine^{​1,2,5,6​}, lysine^​1–4​, cysteine^​1,3,6​, threonine^​3​, glutamine^​6​ and histidine^​6​ residues have been described as acceptor for ADP-ribosylation. ADP-ribosylation increases the molecular mass of the modified protein by 541 Da^​2​. Furthermore, an additional negative charge is introduced into the protein^​1​. The mechanism of mono-ADP-ribosylation is shown in figure 1.

It is assumed that mono-ADP-ribosylation was originally developed by bacteria as a defence mechanism against viruses, other bacterial species and antimicrobial molecules^​3​. Otherwise not much is known about the functions of mono-ADP-ribosylation^​2​.

poly-ADP-ribosylation

Some ADP-ribosyltransferases are able to perform several ADP-ribosylations, which is called poly-ADP-ribosylation. In poly-ADP-ribosylation, further ADP-ribose moieties are added to the already protein-bound ADP-ribose, thus forming ADP-ribose polymers^​4,7​. Chain elongation occurs via a nucleophilic attack of the C2″ hydroxyl of the adenine ribose on the C1″ of the next nicotinamide adenine dinucleotide^​4​. The polymers may be irregularly branched, with a branching point every 20 – 60 units of linear ADP-ribose^​7​. Since each ADP-ribose moiety adds a negative charge to the protein, a protein that previously was positively charged may no longer be charged or may even become negatively charged^​1​. In contrast to mono-ADP-ribosylation, poly-ADP-ribosylation plays a crucial role in various major cellular and biological processes, such as DNA damage repair, cell proliferation and differentiation, metabolism, stress and immune responses^​2,5​.