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.
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PI(3)P contributes to the recruitment of proteins containing PX or FYVE motifs including EEA1 and the NADPH-oxidase subunits p40phox and p47phox.
“PI(3)P also contributes to the recruitment of proteins containing PX or FYVE motifs including EEA1 and the NADPH-oxidase subunits p40phox and p47phox (25–27).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [27]
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- Authors
- Kanai, F., Liu, H., Field, S. J., Akbary, H., Matsuo, T., Brown, G. E., Cantley, L. C., & Yaffe, M. B.
- Affiliations
- Massachusetts Institute of Technology (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Yaffe, Michael B.
- Venue
- Nature Cell Biology
- Published
- 2001-06-12
- Volume
- 3
- Issue
- 7
- Pages
- 675-678
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W1517631297
- Cited by
- 611
- References
- 32
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 14 · 2023: 19 · 2022: 14 · 2021: 24 · 2020: 12 · 2019: 27 · 2018: 18 · 2017: 20 · 2016: 11 · 2015: 13 · 2014: 14 · 2013: 20 · 2012: 25
- FWCI
- 17.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM041890)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- PX domain, p47phox, p40phox, NADPH oxidase, phagocyte NADPH oxidase, phosphatidylinositol 3,4-bisphosphate, phosphatidylinositol 3-phosphate, phosphoinositide binding, phosphatidylinositol 3-kinase, chronic granulomatous disease, early endosomes, neutrophil function, inflammation, signal transduction, membrane protein localization
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Molecular Sequence Data, Phosphoproteins, Transfection, Mutagenesis, Site-Directed, Sequence Alignment, 3T3 Cells, Protein Structure, Tertiary, Phosphatidylinositol Phosphates, NADPH Oxidases, COS Cells, Lipid Metabolism, Mice
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