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Metazoan cell polarity is controlled by a set of highly conserved proteins. Lethal giant larvae (Lgl) functions in apical-basal polarity through phosphorylation-dependent interactions with several other proteins as well as the plasma membrane. Phosphorylation of Lgl by atypical protein kinase C (aPKC), a component of the partitioning-defective (Par) complex in epithelial cells, excludes Lgl from the apical membrane, a crucial step in the establishment of epithelial cell polarity. We present the crystal structures of human Lgl2 in both its unphosphorylated and aPKC-phosphorylated states. Lgl2 adopts a double ?-propeller structure that is unchanged by aPKC phosphorylation of an unstructured loop in its second ?-propeller, ruling out models of phosphorylation-dependent conformational change. Here, we demonstrate that phosphorylation controls the direct binding of purified Lgl2 to negative phospholipids in vitro. We also show that a coil?helix transition of this region that is promoted by phosphatidylinositol 4,5-bisphosphate (PIP<
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2<
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) is also phosphorylation-dependent, implying a highly effective phosphorylative switch for membrane association.<
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