Molecular mechanism of membrane targeting by the

Abstract The general receptor for phosphoinositides iso-form 1 (GRP1) is recruited to the plasma membrane in re-sponse to activation of phosphoinositide 3-kinases and accumulation of phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3]. GRP1ʼs pleckstrin homology (PH) do-main recognizes PtdIns(3,4,5)P3 with high specificity and af-finity, however, the precise mechanism of its association with membranes remains unclear. Here, we detail the mo-lecular basis of membrane anchoring by the GRP1 PH do-main. Our data reveal a multivalent membrane docking involving PtdIns(3,4,5)P3 binding, regulated by pH and fa-cilitated by electrostatic interactions with other anionic lip-ids. The specific recognition of PtdIns(3,4,5)P3 triggers insertion of the GRP1 PH domain into membranes. An acidic environment enhances PtdIns(3,4,5)P3 binding an