The disordered JM of the EGFR contacts the membrane. On growth factor binding, EGFR dimerizes and the juxtamembrane domains fold into helices that dimerize asymmetrically, which leads to asymmetric dimerization of the kinase domains and autophosphorylation (phosphate as yellow circles), which activates downstream signalling. The red box highlights the area shown as the ensemble structure of the ten lowest energy models (grey, PDB 2M20) of the transmembrane and JM regions (right). Residues Arg645-7, Arg651, Lys652 Arg653, Arg656 and Arg657 (blue, sticks) in the JM contact PIP₂ in the membrane (solid black line illustrates the level of the lipid heads).