Interactions of the EphA2 Kinase Domain with a PIP2 containing membrane

Last frames of atomistic simulations revealing the interactions of the transmembrane, juxtamembrane (JM), and kinase domains with the membrane. The structures highlight how the kinase domain is oriented relative to the membrane and how the JM region can modulate this interaction. These structures highlight the role of phosphatidylinositol phosphates (PIPs) in mediating the interaction of the kinase domain with the membrane and, conversely, how positively charged patches at the kinase surface and in the JM region induce the formation of nanoclusters of PIP molecules in the membrane.

Analysis of the orientation of the kinase domain when bound to the PIP₂-containing membrane suggests that there are two main modes of interaction. The predominant binding mode (inter1.pdb) involves the N-terminal lobe of the kinase domain. In this interaction mode, the activation loop of the kinase is accessible to phosphorylation. In the secondary mode (inter2.pdb), the interaction with the bilayer involves both the N- and C-terminal lobes of the kinase and thus the activation loop less accessible.