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ADP‐ribosylation at R125 gates the P2X7 ion channel by presenting a covalent ligand to its nucleotide binding site
Author(s) -
Adriouch Sahil,
Bannas Peter,
Schwarz Nicole,
Fliegert Ralf,
Guse Andreas H.,
Seman Michel,
Haag Friedrich,
KochNoke Friedrich
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-9294com
Subject(s) - gating , chemistry , nad+ kinase , adp ribosylation , nucleotide , transferase , biochemistry , biophysics , enzyme , biology , gene
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. FASEB J . 22, 861–869 (2008)