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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: fj.07-9294comv1 fj.07-9294comv2 22/3/861    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Adriouch, S. Articles by Koch-Nolte, F. PubMed PubMed Citation Articles by Adriouch, S. Articles by Koch-Nolte, F.

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

Sahil Adriouch^*,, Peter Bannas^*, Nicole Schwarz^*, Ralf Fliegert, Andreas H. Guse, Michel Seman, Friedrich Haag^* and Friedrich Koch-Nolte^*,1

^* Institute of Immunology and

Institute of Biochemistry and Molecular Biology I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and

INSERM, U519, Faculté de Médicine et Pharmacie, Université de Rouen, Rouen, France

¹Correspondence: Institute of Immunology, Diagnostic Center, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. E-mail: nolte{at}uke.uni-hamburg.de

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.

Key Words: post-translational modification • purinoceptors • ADP-ribosyltransferases • leukocyte ecto-enzymes