ADP-ribosylation at R125 gates the P2X7 ion channel by presenting a covalent ligand to its nucleotide binding site

• Published in: The FASEB journal Vol. 22; no. 3; pp. 861 - 869
• Main Authors: Adriouch, Sahil, Bannas, Peter, Schwarz, Nicole, Fliegert, Ralf, Guse, Andreas H, Seman, Michel, Haag, Friedrich, Koch-Nolte, Friedrich
• Format: Journal Article
• Language: English
• Published: United States The Federation of American Societies for Experimental Biology 01.03.2008
• Subjects: ADP Ribose Transferases - physiology; Amino Acid Substitution; Arginine - metabolism; Binding Sites - physiology; Cell Line, Tumor; Humans; Ion Channel Gating - physiology; Leukocytes - enzymology; Ligands; Models, Molecular; Nucleotides - metabolism; Protein Processing, Post-Translational; Receptors, Purinergic P2 - physiology; Receptors, Purinergic P2X7
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.07-9294com

ADP-ribosylation is a post-translational modification regulating protein function in which amino acid-specific ADP-ribosyltransferases (ARTs) transfer ADP-ribose from NAD onto specific target proteins. Attachment of the bulky ADP-ribose usually inactivates the target by sterically blocking its interaction with other proteins. P2X7, an ATP-gated ion channel with important roles in inflammation and cell death, in contrast, is activated by ADP-ribosylation. Here, we report the structural basis for this gating and present the first molecular model for the activation of a target protein by ADP-ribosylation. We demonstrate that the ecto-enzyme ART2.2 ADP-ribosylates P2X7 at arginine 125 in a prominent, cysteine-rich region at the interface of 2 receptor subunits. ADP-ribose shares an adenine-ribonculeotide moiety with ATP. Our results indicate that ADP-ribosylation of R125 positions this common chemical framework to fit into the nucleotide-binding site of P2X7 and thereby gates the channel.--Adriouch, S., Bannas, P., Schwarz, N., Fliegert, R., Guse, A. H., Seman, M., Haag, F., Koch-Nolte, F. ADP-ribosylation at R125 gates the P2X7 ion channel by presenting a covalent ligand to its nucleotide binding site.