ADP-ribosylation at R125 gates the P2X7 ion channel by presenting a covalent ligand to its nucleotide binding site
ADP-ribosylation at R125 gates the P2X7 ion channel by presenting a covalent ligand to its nucleotide binding site
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DOI：
10.1096/fj.07-9294com
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发表时间：
2008-03-01
期刊：
影响因子：
4.8
通讯作者：
Koch-Nolte, Friedrich
中科院分区：
文献类型：
--
作者：
Adriouch, Sahil;Bannas, Peter;Koch-Nolte, Friedrich
ADP-核糖基化是一种调节蛋白质功能的翻译后修饰，其中氨基酸特异性 ADP-核糖基转移酶 (ART) 将 ADP-核糖从 NAD 转移到特定的靶蛋白上。庞大的 ADP-核糖的附着通常通过空间阻断其与其他蛋白质的相互作用来使靶标失活。相反，P2X7 是一种 ATP 门控离子通道，在炎症和细胞死亡中发挥重要作用，可通过 ADP 核糖基化激活。在这里，我们报告了这种门控的结构基础，并提出了第一个通过 ADP-核糖基化激活靶蛋白的分子模型。我们证明，胞外酶 ART2.2 ADP 在 2 个受体亚基界面处突出的富含半胱氨酸的区域精氨酸 125 处对 P2X7 进行核糖基化。 ADP-核糖与 ATP 共享腺嘌呤-核糖核苷酸部分。我们的结果表明，R125 的 ADP 核糖基化将这个共同的化学框架定位到 P2X7 的核苷酸结合位点，从而门控通道。
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.