title: Novel Phosphotidylinositol 4,5-Bisphosphate Binding Sites on Focal Adhesion Kinase.
abstract: Focal adhesion kinase (FAK) is a protein tyrosine kinase that is ubiquitously expressed, recruited to focal adhesions, and engages in a variety of cellular signaling pathways. Diverse cellular responses, such as cell migration, proliferation, and survival, are regulated by FAK. Prior to activation, FAK adopts an autoinhibited conformation in which the FERM domain binds the kinase domain, blocking access to the activation loop and substrate binding site. Activation of FAK occurs through conformational change, and acidic phospholipids such as phosphatidylinositol 4,5-bisphosphate (PIP2) are known to facilitate this process. PIP2 binding alters the autoinhibited conformation of the FERM and kinase domains and subsequently exposes the activation loop to phosphorylation. However, the detailed molecular mechanism of PIP2 binding and its role in FAK activation remain unclear. In this study, we conducted coarse-grained molecular dynamics simulations to investigate the binding of FAK to PIP2. Our simulations identified novel areas of basic residues in the kinase domain of FAK that potentially undergo transient binding to PIP2 through electrostatic attractions. Our investigation provides a molecular picture of PIP2-initiated FAK activation and introduces promising new pathways for future studies of FAK regulation.
authors.affiliation: The C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: The C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia, United States of America.
authors.forename: Blake
authors.initials: B
authors.lastname: Mertz
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D051417:Focal Adhesion Kinase 1 / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry*; D010766:Phosphorylation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D055672:Static Electricity
chemical_list: D019269:Phosphatidylinositol 4,5-Diphosphate; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human