Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 43, Pages 21563-21572Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1902790116
Keywords
p75 neurotrophin receptor; membrane oligomeric state; single-molecule microscopy; apoptosis; growth cone collapse
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Funding
- Tuscany Region, Project NOSEISMIC, within Grant POR CRO FSE 2007-2013
- Ministero Universita e Ricerca Projects [PRIN 2009XPTWM2, FIRB RBAP11X42L]
- Fondazione Pisa Project [RST 148/16]
- European Union
- Institutional Scuola Normale Superiore funds
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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.
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