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

Abstract 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...

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Autores principales:	Sergey A. Goncharuk, Lilya E. Artemieva, Kirill D. Nadezhdin, Alexander S. Arseniev, Konstantin S. Mineev
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/93e81a0ed52f4a949f2c31ba9f7ec4c9
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spelling	oai:doaj.org-article:93e81a0ed52f4a949f2c31ba9f7ec4c92021-12-02T18:50:43ZRevising the mechanism of p75NTR activation: intrinsically monomeric state of death domains invokes the "helper" hypothesis10.1038/s41598-020-70721-82045-2322https://doaj.org/article/93e81a0ed52f4a949f2c31ba9f7ec4c92020-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-70721-8https://doaj.org/toc/2045-2322Abstract 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.Sergey A. GoncharukLilya E. ArtemievaKirill D. NadezhdinAlexander S. ArsenievKonstantin S. MineevNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-15 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sergey A. Goncharuk Lilya E. Artemieva Kirill D. Nadezhdin Alexander S. Arseniev Konstantin S. Mineev Revising the mechanism of p75NTR activation: intrinsically monomeric state of death domains invokes the "helper" hypothesis
description	Abstract 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.
format	article
author	Sergey A. Goncharuk Lilya E. Artemieva Kirill D. Nadezhdin Alexander S. Arseniev Konstantin S. Mineev
author_facet	Sergey A. Goncharuk Lilya E. Artemieva Kirill D. Nadezhdin Alexander S. Arseniev Konstantin S. Mineev
author_sort	Sergey A. Goncharuk
title	Revising the mechanism of p75NTR activation: intrinsically monomeric state of death domains invokes the "helper" hypothesis
title_short	Revising the mechanism of p75NTR activation: intrinsically monomeric state of death domains invokes the "helper" hypothesis
title_full	Revising the mechanism of p75NTR activation: intrinsically monomeric state of death domains invokes the "helper" hypothesis
title_fullStr	Revising the mechanism of p75NTR activation: intrinsically monomeric state of death domains invokes the "helper" hypothesis
title_full_unstemmed	Revising the mechanism of p75NTR activation: intrinsically monomeric state of death domains invokes the "helper" hypothesis
title_sort	revising the mechanism of p75ntr activation: intrinsically monomeric state of death domains invokes the "helper" hypothesis
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/93e81a0ed52f4a949f2c31ba9f7ec4c9
work_keys_str_mv	AT sergeyagoncharuk revisingthemechanismofp75ntractivationintrinsicallymonomericstateofdeathdomainsinvokesthehelperhypothesis AT lilyaeartemieva revisingthemechanismofp75ntractivationintrinsicallymonomericstateofdeathdomainsinvokesthehelperhypothesis AT kirilldnadezhdin revisingthemechanismofp75ntractivationintrinsicallymonomericstateofdeathdomainsinvokesthehelperhypothesis AT alexandersarseniev revisingthemechanismofp75ntractivationintrinsicallymonomericstateofdeathdomainsinvokesthehelperhypothesis AT konstantinsmineev revisingthemechanismofp75ntractivationintrinsicallymonomericstateofdeathdomainsinvokesthehelperhypothesis
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Revising the mechanism of p75NTR activation: intrinsically monomeric state of death domains invokes the "helper" hypothesis

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