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...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2020-08-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-020-70721-8 |
| _version_ | 1818422302554980352 |
|---|---|
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T13:24:06Z |
| format | Article |
| id | doaj.art-93e81a0ed52f4a949f2c31ba9f7ec4c9 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T13:24:06Z |
| publishDate | 2020-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-93e81a0ed52f4a949f2c31ba9f7ec4c92022-12-21T22:59:52ZengNature PortfolioScientific Reports2045-23222020-08-0110111510.1038/s41598-020-70721-8Revising the mechanism of p75NTR activation: intrinsically monomeric state of death domains invokes the "helper" hypothesisSergey A. Goncharuk0Lilya E. Artemieva1Kirill D. Nadezhdin2Alexander S. Arseniev3Konstantin S. Mineev4Laboratory of Biomolecular NMR Spectroscopy, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of SciencesLaboratory of Biomolecular NMR Spectroscopy, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of SciencesLaboratory of Biomolecular NMR Spectroscopy, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of SciencesLaboratory of Biomolecular NMR Spectroscopy, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of SciencesLaboratory of Biomolecular NMR Spectroscopy, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of SciencesAbstract 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.https://doi.org/10.1038/s41598-020-70721-8 |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-020-70721-8 |
| work_keys_str_mv | AT sergeyagoncharuk revisingthemechanismofp75ntractivationintrinsicallymonomericstateofdeathdomainsinvokesthehelperhypothesis AT lilyaeartemieva revisingthemechanismofp75ntractivationintrinsicallymonomericstateofdeathdomainsinvokesthehelperhypothesis AT kirilldnadezhdin revisingthemechanismofp75ntractivationintrinsicallymonomericstateofdeathdomainsinvokesthehelperhypothesis AT alexandersarseniev revisingthemechanismofp75ntractivationintrinsicallymonomericstateofdeathdomainsinvokesthehelperhypothesis AT konstantinsmineev revisingthemechanismofp75ntractivationintrinsicallymonomericstateofdeathdomainsinvokesthehelperhypothesis |