InterPro domain: IPR001683

The PX (phox) domain [ 1 ] occurs in a variety of eukaryotic proteins and have been implicated in highly diverse functions such as cell signalling, vesicular trafficking, protein sorting and lipid modification [ 2 , 3 , 4 , 5 ]. PX domains are important phosphoinositide-binding modules that have varying lipid-binding specificities [ 6 ]. The PX domain is approximately 120 residues long [ 7 ], and folds into a three-stranded beta-sheet followed by three -helices and a proline-rich region that immediately preceeds a membrane-interaction loop and spans approximately eight hydrophobic and polar residues. The PX domain of neutrophil cytosol factor 1 (p47phox) binds to the SH3 domain in the same protein [ 8 ]. Phosphorylation of p47(phox), a cytoplasmic activator of the microbicidal phagocyte oxidase (phox), elicits interaction of p47(phox) with phoinositides. The protein phosphorylation-driven conformational change of p47(phox) enables its PX domain to bind to phosphoinositides, the interaction of which plays a crucial role in recruitment of p47(phox) from the cytoplasm to membranes and subsequent activation of the phagocyte oxidase. The lipid-binding activity of this protein is normally suppressed by intramolecular interaction of the PX domain with the C-terminal Src homology 3 (SH3) domain [ 8 ].

The PX domain is conserved from yeast to human. A multiple alignment of representative PX domain sequences from eukaryotic proteins [ 9 ], shows relatively little sequence conservation, although their structure appears to be highly conserved. Although phosphatidylinositol-3-phosphate (PtdIns(3)P) is the primary target of PX domains, binding to phosphatidic acid, phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2), phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), and phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) has been reported as well. The PX-domain is also a protein-protein interaction domain [ 10 ].

1. Novel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3-kinases: binding partners of SH3 domains? Protein Sci. 5, 2353-7
2. Phosphoinositide signaling and the regulation of membrane trafficking in yeast. Trends Biochem. Sci. 25, 229-35
3. The Phox homology (PX) domain, a new player in phosphoinositide signalling. Biochem. J. 360, 513-30
4. Sorting out the cellular functions of sorting nexins. Nat. Rev. Mol. Cell Biol. 3, 919-31
5. The Phox (PX) domain proteins and membrane traffic. Biochim. Biophys. Acta 1761, 878-96
6. The PX domain: a new phosphoinositide-binding module. J. Cell. Sci. 115, 1099-105
7. Solution structure of the PX domain, a target of the SH3 domain. Nat. Struct. Biol. 8, 526-30
8. Binding of the PX domain of p47(phox) to phosphatidylinositol 3,4-bisphosphate and phosphatidic acid is masked by an intramolecular interaction. EMBO J. 21, 5057-68
9. A new method for isolating tyrosine kinase substrates used to identify fish, an SH3 and PX domain-containing protein, and Src substrate. EMBO J. 17, 4346-57
10. The phox homology (PX) domain protein interaction network in yeast. Mol. Cell Proteomics 3, 1053-64