Fast-diffusing p75 ^NTR 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 multifaceted activity of the p75^NTR monomer and let us provide a coherent interpretative frame of existing conflicting data in the literature.