CD95/Fas stoichiometry in future precision medicine

CD95, also known as Fas, belongs to the tumor necrosis factor (TNF) receptor superfamily. The main biological function of this receptor is to orchestrate and control the immune response since mutations in CD95 or deregulation of its downstream signaling pathways lead to auto-immunity and inflammation. Interestingly, more than twenty years ago, pioneer studies highlighted that like TNFR1, TRAILR1 or CD40, CD95 pre-associates at the plasma membrane in a ligand-independent fashion. This self-association occurs through a domain designated pre-ligand assembly domain or PLAD. Although the disruption of this pre-association prevents CD95 signaling, no drugs targeting this region have been generated because many questions remain on the stoichiometry and conformation of this receptor. Despite more than 40.000 publications, no crystal structure of CD95 alone or in combination with its ligand, CD95L, exists. Based on other TNFR members, we herein discuss the predicted conformation of CD95 at the plasma membrane and how these putative structures might account for the induction of the cell signaling pathways.