Structural model for p75 NTR-TrkA intracellular domain interaction: A combined FRET and bioinformatics study
Nerve growth factor (NGF) is a member of the neurotrophins, which are important regulators of embryonic development and adult function in the vertebrate nervous systems. The signaling elicited by NGF regulates diverse activities, including survival, axon growth, and synaptic plasticity. NGF action i...
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todo:paper_00222836_v414_n5_p681_Iacaruso2023-10-03T14:30:23Z Structural model for p75 NTR-TrkA intracellular domain interaction: A combined FRET and bioinformatics study Iacaruso, M.F. Galli, S. Martí, M. Villalta, J.I. Estrin, D.A. Jares-Erijman, E.A. Pietrasanta, L.I. heterodimerization molecular dynamics NGF receptors physical association structural model adaptor protein nerve growth factor nerve growth factor receptor neurotrophin receptor p75 protein tyrosine kinase A animal cell article binding site bioinformatics cell membrane complex formation controlled study dimerization fluorescence resonance energy transfer molecular dynamics nonhuman nuclear magnetic resonance spectroscopy priority journal protein domain protein protein interaction protein structure signal transduction Animals Computational Biology Fluorescence Resonance Energy Transfer Hippocampus Mice Nerve Growth Factor PC12 Cells Protein Binding Protein Interaction Domains and Motifs Rats Receptor, Nerve Growth Factor Receptor, trkA Structural Homology, Protein Vertebrata Nerve growth factor (NGF) is a member of the neurotrophins, which are important regulators of embryonic development and adult function in the vertebrate nervous systems. The signaling elicited by NGF regulates diverse activities, including survival, axon growth, and synaptic plasticity. NGF action is mediated by engagement with two structurally unrelated transmembrane receptors, p75 NTR and TrkA, which are co-expressed in a variety of cells. The functional interactions of these receptors have been widely demonstrated and include complex formation, convergence of signaling pathways, and indirect interaction through adaptor proteins. Each domain of the receptors was shown to be important for the formation of TrkA and p75 NTR complexes, but only the intramembrane and transmembrane domains seemed to be crucial for the creation of high-affinity binding sites. However, whether these occur through a physical association of the receptors is unclear. In the present work, we demonstrate by Förster resonance energy transfer that p75 NTR and TrkA are physically associated through their intracellular (IC) domains and that this interaction occurs predominantly at the cell membrane and prior to NGF stimulation. Our data suggest that there is a pool of receptors dimerized before NGF stimulus, which could contribute to the high-affinity binding sites. We modeled the three-dimensional structure of the TrkA IC domain by homology modeling, and with this and the NMR-resolved structure of p75 NTR, we modeled the heterodimerization of TrkA and p75 NTR by docking methods and molecular dynamics. These models, together with the results obtained by Förster resonance energy transfer, provide structural insights into the receptors' physical association. © 2011 Elsevier Ltd. All rights reserved. Fil:Galli, S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Martí, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Jares-Erijman, E.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00222836_v414_n5_p681_Iacaruso |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
heterodimerization molecular dynamics NGF receptors physical association structural model adaptor protein nerve growth factor nerve growth factor receptor neurotrophin receptor p75 protein tyrosine kinase A animal cell article binding site bioinformatics cell membrane complex formation controlled study dimerization fluorescence resonance energy transfer molecular dynamics nonhuman nuclear magnetic resonance spectroscopy priority journal protein domain protein protein interaction protein structure signal transduction Animals Computational Biology Fluorescence Resonance Energy Transfer Hippocampus Mice Nerve Growth Factor PC12 Cells Protein Binding Protein Interaction Domains and Motifs Rats Receptor, Nerve Growth Factor Receptor, trkA Structural Homology, Protein Vertebrata |
| spellingShingle |
heterodimerization molecular dynamics NGF receptors physical association structural model adaptor protein nerve growth factor nerve growth factor receptor neurotrophin receptor p75 protein tyrosine kinase A animal cell article binding site bioinformatics cell membrane complex formation controlled study dimerization fluorescence resonance energy transfer molecular dynamics nonhuman nuclear magnetic resonance spectroscopy priority journal protein domain protein protein interaction protein structure signal transduction Animals Computational Biology Fluorescence Resonance Energy Transfer Hippocampus Mice Nerve Growth Factor PC12 Cells Protein Binding Protein Interaction Domains and Motifs Rats Receptor, Nerve Growth Factor Receptor, trkA Structural Homology, Protein Vertebrata Iacaruso, M.F. Galli, S. Martí, M. Villalta, J.I. Estrin, D.A. Jares-Erijman, E.A. Pietrasanta, L.I. Structural model for p75 NTR-TrkA intracellular domain interaction: A combined FRET and bioinformatics study |
| topic_facet |
heterodimerization molecular dynamics NGF receptors physical association structural model adaptor protein nerve growth factor nerve growth factor receptor neurotrophin receptor p75 protein tyrosine kinase A animal cell article binding site bioinformatics cell membrane complex formation controlled study dimerization fluorescence resonance energy transfer molecular dynamics nonhuman nuclear magnetic resonance spectroscopy priority journal protein domain protein protein interaction protein structure signal transduction Animals Computational Biology Fluorescence Resonance Energy Transfer Hippocampus Mice Nerve Growth Factor PC12 Cells Protein Binding Protein Interaction Domains and Motifs Rats Receptor, Nerve Growth Factor Receptor, trkA Structural Homology, Protein Vertebrata |
| description |
Nerve growth factor (NGF) is a member of the neurotrophins, which are important regulators of embryonic development and adult function in the vertebrate nervous systems. The signaling elicited by NGF regulates diverse activities, including survival, axon growth, and synaptic plasticity. NGF action is mediated by engagement with two structurally unrelated transmembrane receptors, p75 NTR and TrkA, which are co-expressed in a variety of cells. The functional interactions of these receptors have been widely demonstrated and include complex formation, convergence of signaling pathways, and indirect interaction through adaptor proteins. Each domain of the receptors was shown to be important for the formation of TrkA and p75 NTR complexes, but only the intramembrane and transmembrane domains seemed to be crucial for the creation of high-affinity binding sites. However, whether these occur through a physical association of the receptors is unclear. In the present work, we demonstrate by Förster resonance energy transfer that p75 NTR and TrkA are physically associated through their intracellular (IC) domains and that this interaction occurs predominantly at the cell membrane and prior to NGF stimulation. Our data suggest that there is a pool of receptors dimerized before NGF stimulus, which could contribute to the high-affinity binding sites. We modeled the three-dimensional structure of the TrkA IC domain by homology modeling, and with this and the NMR-resolved structure of p75 NTR, we modeled the heterodimerization of TrkA and p75 NTR by docking methods and molecular dynamics. These models, together with the results obtained by Förster resonance energy transfer, provide structural insights into the receptors' physical association. © 2011 Elsevier Ltd. All rights reserved. |
| format |
JOUR |
| author |
Iacaruso, M.F. Galli, S. Martí, M. Villalta, J.I. Estrin, D.A. Jares-Erijman, E.A. Pietrasanta, L.I. |
| author_facet |
Iacaruso, M.F. Galli, S. Martí, M. Villalta, J.I. Estrin, D.A. Jares-Erijman, E.A. Pietrasanta, L.I. |
| author_sort |
Iacaruso, M.F. |
| title |
Structural model for p75 NTR-TrkA intracellular domain interaction: A combined FRET and bioinformatics study |
| title_short |
Structural model for p75 NTR-TrkA intracellular domain interaction: A combined FRET and bioinformatics study |
| title_full |
Structural model for p75 NTR-TrkA intracellular domain interaction: A combined FRET and bioinformatics study |
| title_fullStr |
Structural model for p75 NTR-TrkA intracellular domain interaction: A combined FRET and bioinformatics study |
| title_full_unstemmed |
Structural model for p75 NTR-TrkA intracellular domain interaction: A combined FRET and bioinformatics study |
| title_sort |
structural model for p75 ntr-trka intracellular domain interaction: a combined fret and bioinformatics study |
| url |
http://hdl.handle.net/20.500.12110/paper_00222836_v414_n5_p681_Iacaruso |
| work_keys_str_mv |
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