The phosphoinositide binding Phox Homology domain of Tc10/Cdc42 GTPase-activating 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. TCGAP (Tc10/Cdc42 GTPase-activating protein) contains N-terminal PX and Src Homology 3 (SH3) domains, a central Rho GAP domain, and C-terminal proline-rich regions. It is widely expressed in the brain where it is involved in regulating the outgrowth of axons and dendrites and is regulated by the protein tyrosine kinase Fyn. It interacts with cdc42 and TC10beta through its GAP domain and with phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] through its PX domain. It is translocated to the plasma membrane in adipocytes in response to insulin and may be involved in the regulation of insulin-stimulated glucose transport. TCGAP has also been named sorting nexins 26 (SNX26). SNXs make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. It is unknown whether TCGAP also functions as a SNX.
Feature 1:putative phosphoinositide binding site [chemical binding site]
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.