FLAP, sequence and structure analysis. A, electrostatic surface potential of full-length insect ERM protein (PDB 2I1K) and B, of unmasked moesin FERM domain with color charge scale on the left. The molecules are oriented to show the PIP2 binding POCKET, which is covered by the FLAP in the closed conformation of moesin (A) and uncovered in the FERM domain (B). Labels indicate locations of the A, B, and C lobes. Location of PIP2 binding POCKET is indicated by arrows. C, ribbon representation of the closed ERM structure. FLAP is red (N-terminal and C-terminal parts) or magenta (reconstructed tip, amino acids 473–485). β1 to β4 strands of the PH-like domain are green; β5-β7 strands are yellow; α-helix is blue. C-terminal tail is light blue. Light Blue circles indicate locations of the two critical residues, Lys-63 and Lys-278, in the POCKET, which are masked by the FLAP when moesin is closed. D, multiple sequence analysis of the FLAP of human ezrin, radixin, and moesin and flanking regions. Red dashed rectangle highlights the FLAP. Above the sequence is a row of symbols that scores the extent of sequence conservation scored by ClustalX (* = identity; : = all residues belong to a strong conservation group; · = all residues belong to a weak conservation group). Arrowheads indicate residues in moesin that are acidic (red) or short side chains (black). Statistical significance compared with Moesin WT membrane enrichment is shown as: *, p < 0.1 and **, p < 0.01.