Structural basis of Focal Adhesion Kinase activation on lipid membranes.

Focal Adhesion Kinase (FAK) is a key component of the membrane-proximal signaling layer in focal adhesions, regulating important processes, including cell migration, proliferation and survival. In the cytosol, FAK adopts an autoinhibited state but is activated upon recruitment into focal adhesions, yet how this occurs or what induces structural changes is unknown. Here, we employ cryo-electron microscopy to reveal how FAK associates with lipid membranes and how membrane interactions unlock FAK autoinhibition to promote activation. Intriguingly, initial binding of FAK to the membrane causes steric clashes that release the kinase domain from autoinhibition, allowing it to rearrange and interact itself with the membrane in an orientation that places the active site towards the membrane. In this conformation the autophosphorylation site is exposed and multiple interfaces align to promote FAK oligomerization. We show that interfaces responsible for initial dimerization and membrane attachment are essential for FAK autophosphorylation and cellular activity including cancer cell invasion, whilst stable FAK oligomerization appears to be needed for optimal cancer cell proliferation in an anchorage-independent manner.