Phox homology
IPR001683
Definition
The PX (phox) domain PMID:8931154 occurs in a variety of eukaryotic proteins and has been implicated in highly diverse functions, including cell signalling, vesicular trafficking, protein sorting and lipid modification [[cite:PMID:10782093], [cite:PMID:11736640], [cite:PMID:12461558], [cite:PMID:16782399]]. PX domains are important phosphoinositide-binding modules that exhibit varying lipid-binding specificities PMID:11884510. The PX domain is approximately 120 residues in length PMID:11373621 and folds into a three-stranded β-sheet followed by three α-helices and a proline-rich region. This region immediately precedes 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 within the same protein PMID:11373621. Phosphorylation of p47(phox), a cytoplasmic activator of the microbicidal phagocyte oxidase (phox), triggers interaction of p47(phox) with phosphoinositides. This phosphorylation-driven conformational change enables the PX domain to bind phosphoinositides, an interaction that plays a crucial role in the 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 between the PX domain and the C-terminal Src homology 3 (SH3) domain PMID:12356722. The PX domain is conserved from yeast to humans. Multiple alignment of representative PX domain sequences from eukaryotic proteins PMID:9687503 reveals relatively little sequence conservation, although the overall structure appears to be highly conserved. While 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 also been reported. The PX domain additionally functions as a protein-protein interaction domain PMID:15263065. This domain is found in Sorting nexin and related proteins. Sorting nexins (SNXs) are a diverse family of proteins characterised by the presence of a phosphoinositide-binding PX domain, which mediates their association with endosomal membranes. They play essential roles in membrane trafficking, endosomal sorting and signal transduction across eukaryotes. SNX1 functions in retrograde transport from endosomes to the trans-Golgi network as a core component of the retromer complex, facilitating the retrieval of cargo receptors such as the cation-independent mannose-6-phosphate receptor PMID:17101778. SNX2 shares functional similarity with SNX1 and also participates in retromer-mediated retrograde trafficking, with partial redundancy between the two proteins in endosome-to-Golgi transport PMID:17101778. SNX3 is a smaller sorting nexin that regulates the recycling of specific cargo proteins, including Wntless, which is essential for Wnt secretion [[cite:PMID:21725319], [cite:PMID:22041890]], and transferrin receptor, thereby contributing to iron homeostasis PMID:23416069. SNX4 is involved in endosomal recycling pathways, where it promotes transferrin receptor recycling and prevents its degradation PMID:17994011, and additionally participates in autophagosome assembly by regulating the trafficking of the phospholipid scramblase ATG9A [[cite:PMID:32513819], [cite:PMID:33468622]].
48 human proteins with this domain
Each is a reviewed human protein in the Seroatlas serome and a potential autoantibody target; this domain groups them into one antibody-relevant category. Every entry links to its own record.
Loading the interactive Seroatlas explorer...