Membrane recognition and substrate binding mechanism of PIP4Kγ kinase from molecular simulations

Abstract

PIP4Kγ belongs to a family of lipid kinases that use phosphatidylinositol-5-phosphate (PI5P) as a substrate to produce phosphatidylinositol-4,5-biphosphate, and has recently emerged as a neurodegenerative disease therapeutic target. However, the underlying structural basis of membrane recognition and substrate binding largely remains unknown as there is no crystal structure of the substrate-bound lipid kinase. Moreover, the key structural elements suggested to be involved in substrate binding and recognition, the DLKGS motif and the activation loop region as well as the ATP binding site, are not resolved in the PIP4Kγ crystal structure.