Full-length p40phox structure suggests a basis for regulation mechanism of its membrane binding
Full-length p40phox structure suggests a basis for regulation mechanism of its membrane binding
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DOI：
10.1038/sj.emboj.7601561
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发表时间：
2007-02-21
期刊：
影响因子：
11.4
通讯作者：
Inagaki, Fuyuhiko
中科院分区：
文献类型：
--
作者：
Honbou, Kazuya;Minakami, Reiko;Inagaki, Fuyuhiko
产生超氧化物的吞噬细胞NADPH氧化酶在吞噬过程中被激活，以破坏摄入的微生物。接合蛋白p40（phox）通过PB1结构域与必需氧化酶激活剂p67（phox）结合，并被认为通过将p67（phox）招募到吞噬体中起作用；在这个过程中，p40（phox）的PX结构域与吞噬体膜中丰富的脂质磷脂酰肌醇3-磷酸[PtdIns(3) P]结合。在体内和体外，我们发现p40（phox）的PtdIns(3) p结合活性通常被PB1结构域抑制。全长p40phox的晶体结构表明，这种抑制作用是通过PB1和PX结构域的分子内相互作用介导的。p40(phox) PB1结构域与PX结构域的界面位于p67phox PB1结构域的相反一侧，因此PB1介导的PX调控发生在不阻止PB1-PB1与p67（phox）结合的情况下。
The superoxide-producing phagocyte NADPH oxidase is activated during phagocytosis to destroy ingested microbes. The adaptor protein p40(phox) associates via the PB1 domain with the essential oxidase activator p67(phox), and is considered to function by recruiting p67(phox) to phagosomes; in this process, the PX domain of p40(phox) binds to phosphatidylinositol 3-phosphate [ PtdIns(3) P], a lipid abundant in the phagosomal membrane. Here we show that the PtdIns(3) P-binding activity of p40(phox) is normally inhibited by the PB1 domain both in vivo and in vitro. The crystal structure of the full-length p40phox reveals that the inhibition is mediated via intramolecular interaction between the PB1 and PX domains. The interface of the p40(phox) PB1 domain for the PX domain localizes on the opposite side of that for the p67phox PB1 domain, and thus the PB1-mediated PX regulation occurs without preventing the PB1-PB1 association with p67(phox).