Structural basis for the association of PLEKHA7 with membrane-embedded phosphatidylinositol lipids

PLEKHA7 (pleckstrin homology domain containing family A member 7) plays key roles in intracellular signaling, cytoskeletal organization, and cell adhesion, and is associated with multiple human cancers. The interactions of its pleckstrin homology (PH) domain with membrane phosphatidyl-inositol-phosphate (PIP) lipids are critical for proper cellular localization and function, but little is known about how PLEKHA7 and other PH domains interact with membrane-embedded PIPs. Here we describe the structural basis for recognition of membrane-bound PIPs by PLEHA7. Using X-ray crystallography, nuclear magnetic resonance, molecular dynamics simulations, and isothermal titration calorimetry, we show that the interaction of PLEKHA7 with PIPs is multivalent, distinct from a discrete one-to-one interaction, and induces PIP clustering. Our findings reveal a central role of the membrane assembly in mediating protein-PIP association and provide a roadmap for understanding how the PH domain contributes to the signaling, adhesion, and nanoclustering functions of PLEKHA7. [Display omitted] •The structure of the PLEHA7 PH domain reveals multiple binding sites for PIP lipids•The PH domain contains major elements of PIP recognition by PLEKHA7•The membrane scaffold promotes multivalent association of one PH domain with PIPs•The PLEKHA7 PH domain induces membrane PIP clustering The interactions of PLEKHA7 with membrane-bound phosphatidylinositol (PIP) lipids are critical for cell signaling and cytoskeletal organization. Here, we describe the structural basis for PIP recognition by its PH domain and provide a roadmap for understanding how this contributes to the functions of PLEKHA7.