Fast-diffusing p75 NTR monomers support apoptosis and growth cone collapse by neurotrophin ligands

Proc Natl Acad Sci U S A. 2019 Oct 22;116(43):21563-21572. doi: 10.1073/pnas.1902790116. Epub 2019 Sep 12.

Abstract

The p75 neurotrophin (NT) receptor (p75NTR) 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 p75NTR activation by NT ligands is still missing. Here, we present a single-molecule study of membrane p75NTR 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) p75NTR are almost identical to those of a receptor mutant lacking residues previously believed to induce oligomerization. The wt p75NTR and mutated (mut) p75NTR 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 p75NTR , but not of mut p75NTR, to mediate immature NT (proNT)-induced apoptosis. Both p75NTR 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 p75NTR monomer and let us provide a coherent interpretative frame of existing conflicting data in the literature.

Keywords: apoptosis; growth cone collapse; membrane oligomeric state; p75 neurotrophin receptor; single-molecule microscopy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Cell Line
  • Cell Membrane / metabolism
  • Growth Cones / physiology*
  • Humans
  • Mice
  • Mice, Knockout
  • Nerve Growth Factors / metabolism*
  • Nervous System / metabolism
  • Nervous System Physiological Phenomena / genetics
  • Receptor, Nerve Growth Factor / genetics
  • Receptor, Nerve Growth Factor / metabolism*

Substances

  • Nerve Growth Factors
  • Receptor, Nerve Growth Factor