Structural basis of phosphatidylserine enhancement of Gas6 ligand-induced Axl activation

TAMs (Tyro3, Axl, and MerTK) are receptor tyrosine kinases with primary roles in apoptotic clearance and immune suppression. In apoptosis, bridging complexes form between TAM receptors on phagocytic cells and TAM ligands bound to phosphatidylserine exposed on the surface of dying cells, but how these complexes form or why lipid is required for receptor activation is poorly understood. We present the first structures of a complete TAM receptor (Axl) and ligand (Gas6) 2:2 bridging complex with and without lipid, which suggest that the lipid functions to stabilize and promote active complexes. We also observe a stable 1:1 complex, presumed to be inactive, and provide evidence that these complexes are conversely able to form higher-order oligomers. We propose a mechanism for how lipids promote TAM receptor activation, providing a structural and biochemical basis for developing therapies that selectively target the lipid-dependent, immunosuppressive arm of TAM signaling exploited by tumors.