Detection of p75NTR trimers: implications for receptor stoichiometry and function

AGUSTÍN ANASTASÍA GONZALEZ; OLAV OLSEN; MARC TESSIER-LAVIGNE; PHILIP A. BARKER; MOSES V. CHAO; BARBARA L. HEMPSTEAD

Newport

Congreso; Neurotrophic Factors Gordon Conference; 2015

Gordon Research Conferences

The p75 neurotrophin receptor (p75NTR) 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, p75NTR interacts with dimeric ligands (i.e. proneurotrophins or mature neurotrophins), but several of the intracellular adaptors that mediate p75NTR signaling are trimeric (i.e. TNF receptor associated factor 6 or TRAF6). Consequently, the active receptor signaling unit remains uncertain. To identify the functional receptor complex, we evaluated its oligomerization utilizing a combination of biochemical techniques. We found that the most abundant homotypic arrangement for p75NTR is a trimer. Interestingly, monomers and trimers co-exist at the cell surface, but dimers are low in level and only detected after chemical crosslinking. Interestingly, trimers are not required for ligand-independent or ligand-dependent p75NTR activation in a growth cone retraction functional assay. However, monomers and/or dimers are capable of inducing acute morphological effects in neurons. Moreover, we found that p75NTR interacts with death receptor 6 (DR6), but this association is not required for p75 activation in the growth cone retraction assay. We propose that p75NTR activation is regulated by its oligomerization status and its levels of expression. These results indicate that the oligomeric state of p75NTR confers differential responses and offers an explanation for the diverse and contradictory actions of this receptor in the nervous system.