title: ADP-ribosylation at R125 gates the P2X7 ion channel by presenting a covalent ligand to its nucleotide binding site.
abstract: 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-ribonucleotide 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.
authors.affiliation: Institute of Immunology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
authors.forename: Sahil
authors.initials: S
authors.lastname: Adriouch
authors.forename: Peter
authors.initials: P
authors.lastname: Bannas
authors.forename: Nicole
authors.initials: N
authors.lastname: Schwarz
authors.forename: Ralf
authors.initials: R
authors.lastname: Fliegert
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Guse
authors.forename: Michel
authors.initials: M
authors.lastname: Seman
authors.forename: Friedrich
authors.initials: F
authors.lastname: Haag
authors.forename: Friedrich
authors.initials: F
authors.lastname: Koch-Nolte
mesh_terms: D036002:ADP Ribose Transferases / Q000502:physiology*; D019943:Amino Acid Substitution; D001120:Arginine / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D007962:Leukocytes / Q000201:enzymology; D008024:Ligands; D008958:Models, Molecular; D009711:Nucleotides / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058486:Receptors, Purinergic P2X7
chemical_list: D008024:Ligands; D009711:Nucleotides; C546468:P2RX7 protein, human; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D001120:Arginine; D036002:ADP Ribose Transferases