Revising the mechanism of p75NTR activation: intrinsically monomeric state of death domains invokes the "helper" hypothesis.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Mutation*; Nerve Tissue Proteins/*chemistry ; Nerve Tissue Proteins/*metabolism ; Receptors, Growth Factor/*chemistry ; Receptors, Growth Factor/*metabolism ; Receptors, Nerve Growth Factor/*chemistry ; Receptors, Nerve Growth Factor/*metabolism; Animals ; Humans ; Ligands ; Liposomes/metabolism ; Models, Molecular ; Nerve Tissue Proteins/genetics ; Protein Binding ; Protein Conformation ; Protein Domains ; Protein Multimerization ; Rats ; Receptors, Growth Factor/genetics ; Receptors, Nerve Growth Factor/genetics

The neurotrophin receptor p75NTR plays crucial roles in neuron development and regulates important neuronal processes like degeneration, apoptosis and cell survival. At the same time the detailed mechanism of signal transduction is unclear. One of the main hypotheses known as the snail-tong mechanism assumes that in the inactive state, the death domains interact with each other and in response to ligand binding there is a conformational change leading to their exposure. Here, we show that neither rat nor human p75NTR death domains homodimerize in solution. Moreover, there is no interaction between the death domains in a more native context: the dimerization of transmembrane domains in liposomes and the presence of activating mutation in extracellular juxtamembrane region do not lead to intracellular domain interaction. These findings suggest that the activation mechanism of p75NTR should be revised. Thus, we propose a novel model of p75NTR functioning based on interaction with "helper" protein.

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0 (Ligands)
0 (Liposomes)
0 (NGFR protein, human)
0 (Nerve Tissue Proteins)
0 (Receptors, Growth Factor)
0 (Receptors, Nerve Growth Factor)
136958-07-1 (Ngfr protein, rat)

Date Created: 20200815 Date Completed: 20210111 Latest Revision: 20210813

20221213

PMC7427093

10.1038/s41598-020-70721-8

32792564