Journal
JOURNAL OF NEUROSCIENCE
Volume 35, Issue 34, Pages 11911-11920Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0591-15.2015
Keywords
p75(NTR); proNGF; signaling unit; stoichiometry; TNF receptor; trimerization
Categories
Funding
- National Institutes of Health [NS21072, AG025970, HD23315, NS030687, NS070173, NS064114]
- Canadian Institutes for Health Research Grant [325420]
- IBRO Return Home Fellowship
- ISN-CAEN Return Home Award
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The p75 neurotrophin receptor (p75(NTR)) is a multifunctional receptor that participates in many critical processes in the nervous system, ranging from apoptosis to synaptic plasticity and morphological events. It is a member of the tumor necrosis factor receptor (TNFR) superfamily, whose members undergo trimeric oligomerization. Interestingly, p75(NTR) interacts with dimeric ligands (i.e., proneurotrophins or mature neurotrophins), but several of the intracellular adaptors that mediate p75(NTR) signaling are trimeric (i.e., TNFR-associated factor 6 or TRAF6). Consequently, the active receptor signaling unit remains uncertain. To identify the functional receptor complex, we evaluated its oligomerization in vitro and in mice brain tissues using a combination of biochemical techniques. We found that the most abundant homotypic arrangement for p75(NTR) is a trimer and that monomers and trimers coexist at the cell surface. Interestingly, trimers are not required for ligand-independent or ligand-dependent p75(NTR) activation in a growth cone retraction functional assay. However, monomers are capable of inducing acute morphological effects in neurons. We propose that p75(NTR) activation is regulated by its oligomerization status and its levels of expression. These results indicate that the oligomeric state of p75(NTR) confers differential responses and offers an explanation for the diverse and contradictory actions of this receptor in the nervous system.
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