Fast-diffusing p75NTR monomers support apoptosis and growth cone collapse by neurotrophin ligands

The p75 neurotrophin (NT) receptor (p75(NTR)) plays a crucial role in balancing survival-versus-death decisions in the nervous system. Yet, despite 2 decades of structural and biochemical studies, a comprehensive, accepted model for p75(NTR) activation by NT ligands is still missing. Here, we present a single-molecule study of membrane p75(NTR) in living cells, demonstrating that the vast majority of receptors are monomers before and after NT activation. Interestingly, the stoichiometry and diffusion properties of the wild-type (wt) p75(NTR) are almost identical to those of a receptor mutant lacking residues previously believed to induce oligomerization. The wt p75(NTR) and mutated (mut) p75(NTR) differ in their partitioning in cholesterol-rich membrane regions upon nerve growth factor (NGF) stimulation: We argue that this is the origin of the ability of wt p75(NTR), but not of mut p75(NTR), to mediate immature NT (proNT)-induced apoptosis. Both p75(NTR) forms support proNT-induced growth cone retraction: We show that receptor surface accumulation is the driving force for cone collapse. Overall, our data unveil the multi-faceted activity of the p75(NTR) monomer and let us provide a coherent interpretative frame of existing conflicting data in the literature.