|2dyb, resolution 3.15Å ()|
The crystal structure of human p40(phox)
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.
Full-length p40phox structure suggests a basis for regulation mechanism of its membrane binding., Honbou K, Minakami R, Yuzawa S, Takeya R, Suzuki NN, Kamakura S, Sumimoto H, Inagaki F, EMBO J. 2007 Feb 21;26(4):1176-86. Epub 2007 Feb 8. PMID:17290225
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[NCF4_HUMAN] Defects in NCF4 are the cause of chronic granulomatous disease autosomal recessive cytochrome-b-positive type 3 (CGD3) [MIM:613960]. CGD3 is a disorder characterized by the inability of neutrophils and phagocytes to kill microbes that they have ingested. Patients suffer from life-threatening bacterial/fungal infections.
[NCF4_HUMAN] Component of the NADPH-oxidase, a multicomponent enzyme system responsible for the oxidative burst in which electrons are transported from NADPH to molecular oxygen, generating reactive oxidant intermediates. It may be important for the assembly and/or activation of the NADPH-oxidase complex.
About this Structure
- Honbou K, Minakami R, Yuzawa S, Takeya R, Suzuki NN, Kamakura S, Sumimoto H, Inagaki F. Full-length p40phox structure suggests a basis for regulation mechanism of its membrane binding. EMBO J. 2007 Feb 21;26(4):1176-86. Epub 2007 Feb 8. PMID:17290225
- ↑ Matute JD, Arias AA, Wright NA, Wrobel I, Waterhouse CC, Li XJ, Marchal CC, Stull ND, Lewis DB, Steele M, Kellner JD, Yu W, Meroueh SO, Nauseef WM, Dinauer MC. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. Blood. 2009 Oct 8;114(15):3309-15. doi: 10.1182/blood-2009-07-231498. Epub 2009, Aug 19. PMID:19692703 doi:10.1182/blood-2009-07-231498