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  • The EMBO Journal (2007) 26, 1176 - 1186
  • doi:10.1038/sj.emboj.7601561

Published online: 8 February 2007

Full-length p40phox structure suggests a basis for regulation mechanism of its membrane binding

Kazuya Honbou1,a, Reiko Minakami2,3,a, Satoru Yuzawa1, Ryu Takeya2,4, Nobuo N Suzuki1, Sachiko Kamakura2,4, Hideki Sumimoto2,4 and Fuyuhiko Inagaki1

  1. Laboratory of Structural Biology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
  2. Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
  3. Department of Health Sciences, School of Medicine, Kyushu University, Fukuoka, Japan
  4. CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan

Correspondence to:

Hideki Sumimoto, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan. Tel.: +81 92 642 6806; Fax: +81 92 642 6807; E-mail: hsumi@bioreg.kyushu-u.ac.jp

Fuyuhiko Inagaki, Laboratory of Structural Biology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan. Tel.: +81 11 706 9011; Fax: +81 11 706 9012; E-mail: finagaki@pharm.hokudai.ac.jp

aThese authors contributed equally to this work

Received 28 September 2006; Accepted 19 December 2006

The superoxide-producing phagocyte NADPH oxidase is activated during phagocytosis to destroy ingested microbes. The adaptor protein p40phox associates via the PB1 domain with the essential oxidase activator p67phox, and is considered to function by recruiting p67phox to phagosomes; in this process, the PX domain of p40phox 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 p40phox 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 p40phox 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 p67phox.

  • Keywords:

    • crystal structure,
    • NADPH oxidase,
    • p40phox,
    • PtdIns(3)P,
    • PX domain