title: The PX domains of p47phox and p40phox bind to lipid products of PI(3)K.
abstract: PX domains are found in a variety of proteins that associate with cell membranes, but their molecular function has remained obscure. We show here that the PX domains in p47phox and p40phox subunits of the phagocyte NADPH oxidase bind to phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P(2)) and phosphatidylinositol-3-phosphate (PtdIns(3)P), respectively. We also show that an Arg-to-Gln mutation in the PX domain of p47phox, which is found in patients with chronic granulomatous disease, eliminates phosphoinositide binding, as does the analogous mutation in the PX domain of p40phox. The PX domain of p40phox localizes specifically to PtdIns(3)P-enriched early endosomes, and this localization is disrupted by inhibition of phosphoinositide-3-OH kinase (PI(3)K) or by the Arg-to-Gln point mutation. These findings provide a molecular foundation to understand the role of PI(3)K in regulating neutrophil function and inflammation, and to identify PX domains as specific phosphoinositide-binding modules involved in signal transduction events in eukaryotic cells.
authors: Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors: F
authors: F
authors: Kanai
authors: H
authors: H
authors: Liu
authors: S J
authors: SJ
authors: Field
authors: H
authors: H
authors: Akbary
authors: T
authors: T
authors: Matsuo
authors: G E
authors: GE
authors: Brown
authors: L C
authors: LC
authors: Cantley
authors: M B
authors: MB
authors: Yaffe
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D050356:Lipid Metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019255:NADPH Oxidases; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D014162:Transfection
chemical_list: D018129:Phosphatidylinositol Phosphates; D010750:Phosphoproteins; C085072:neutrophil cytosol factor 40K; C055525:phosphatidylinositol 3-phosphate; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1