The phosphoinositide binding Phox Homology domain of Five SH protein
The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. Five SH (FISH), also called Tks5, is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells. FISH contains an N-terminal PX domain and five Src homology 3 (SH3) domains. FISH binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion. This subfamily also includes proteins with a different number of SH3 domains than FISH, such as Tks4, which contains four SH3 domains instead of five. The Tks4 adaptor protein is required for the formation of functional podosomes. It has overlapping, but not identical, functions as FISH. The PX domain is involved in targeting of proteins to PI-enriched membranes, and may also be involved in protein-protein interaction.
Feature 1:phosphoinositide binding site [chemical binding site]
Evidence:
Comment:A majority of PX domain containing proteins binds phosphatidylinositol-3-phosphate (PI3P) at this site. In some cases, other phosphoinositides, such as PI4P or PI(3,4)P2, are the preferred substrates.
Comment:based on the structures of phosphatidylinositol-3-phosphate bound to other members of this superfamily
Comment:Two basic residues are key in binding with phosphoinositides: one forms hydrogen bonds with the 3-phosphate of PI(3)P and another forms hydrogen bonds with the 4-and 5-hydroxyl groups of PI(3)P.