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Allosteric activation of preformed EGF receptor dimers by a single ligand binding event
Aberrant activation of the epidermal growth factor receptor (EGFR) by mutations has been implicated in a variety of human cancers. Elucidation of the structure of the full-length receptor is essential to understand the molecular mechanisms underlying its activation. Unlike previously anticipated, he...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9748436/ https://www.ncbi.nlm.nih.gov/pubmed/36531494 http://dx.doi.org/10.3389/fendo.2022.1042787 |
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author | Purba, Endang R. Saita, Ei-ichiro Akhouri, Reetesh R. Öfverstedt, Lars-Goran Wilken, Gunnar Skoglund, Ulf Maruyama, Ichiro N. |
author_facet | Purba, Endang R. Saita, Ei-ichiro Akhouri, Reetesh R. Öfverstedt, Lars-Goran Wilken, Gunnar Skoglund, Ulf Maruyama, Ichiro N. |
author_sort | Purba, Endang R. |
collection | PubMed |
description | Aberrant activation of the epidermal growth factor receptor (EGFR) by mutations has been implicated in a variety of human cancers. Elucidation of the structure of the full-length receptor is essential to understand the molecular mechanisms underlying its activation. Unlike previously anticipated, here, we report that purified full-length EGFR adopts a homodimeric form in vitro before and after ligand binding. Cryo-electron tomography analysis of the purified receptor also showed that the extracellular domains of the receptor dimer, which are conformationally flexible before activation, are stabilized by ligand binding. This conformational flexibility stabilization most likely accompanies rotation of the entire extracellular domain and the transmembrane domain, resulting in dissociation of the intracellular kinase dimer and, thus, rearranging it into an active form. Consistently, mutations of amino acid residues at the interface of the symmetric inactive kinase dimer spontaneously activate the receptor in vivo. Optical observation also indicated that binding of only one ligand activates the receptor dimer on the cell surface. Our results suggest how oncogenic mutations spontaneously activate the receptor and shed light on the development of novel cancer therapies. |
format | Online Article Text |
id | pubmed-9748436 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97484362022-12-15 Allosteric activation of preformed EGF receptor dimers by a single ligand binding event Purba, Endang R. Saita, Ei-ichiro Akhouri, Reetesh R. Öfverstedt, Lars-Goran Wilken, Gunnar Skoglund, Ulf Maruyama, Ichiro N. Front Endocrinol (Lausanne) Endocrinology Aberrant activation of the epidermal growth factor receptor (EGFR) by mutations has been implicated in a variety of human cancers. Elucidation of the structure of the full-length receptor is essential to understand the molecular mechanisms underlying its activation. Unlike previously anticipated, here, we report that purified full-length EGFR adopts a homodimeric form in vitro before and after ligand binding. Cryo-electron tomography analysis of the purified receptor also showed that the extracellular domains of the receptor dimer, which are conformationally flexible before activation, are stabilized by ligand binding. This conformational flexibility stabilization most likely accompanies rotation of the entire extracellular domain and the transmembrane domain, resulting in dissociation of the intracellular kinase dimer and, thus, rearranging it into an active form. Consistently, mutations of amino acid residues at the interface of the symmetric inactive kinase dimer spontaneously activate the receptor in vivo. Optical observation also indicated that binding of only one ligand activates the receptor dimer on the cell surface. Our results suggest how oncogenic mutations spontaneously activate the receptor and shed light on the development of novel cancer therapies. Frontiers Media S.A. 2022-11-30 /pmc/articles/PMC9748436/ /pubmed/36531494 http://dx.doi.org/10.3389/fendo.2022.1042787 Text en Copyright © 2022 Purba, Saita, Akhouri, Öfverstedt, Wilken, Skoglund and Maruyama https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Endocrinology Purba, Endang R. Saita, Ei-ichiro Akhouri, Reetesh R. Öfverstedt, Lars-Goran Wilken, Gunnar Skoglund, Ulf Maruyama, Ichiro N. Allosteric activation of preformed EGF receptor dimers by a single ligand binding event |
title | Allosteric activation of preformed EGF receptor dimers by a single ligand binding event |
title_full | Allosteric activation of preformed EGF receptor dimers by a single ligand binding event |
title_fullStr | Allosteric activation of preformed EGF receptor dimers by a single ligand binding event |
title_full_unstemmed | Allosteric activation of preformed EGF receptor dimers by a single ligand binding event |
title_short | Allosteric activation of preformed EGF receptor dimers by a single ligand binding event |
title_sort | allosteric activation of preformed egf receptor dimers by a single ligand binding event |
topic | Endocrinology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9748436/ https://www.ncbi.nlm.nih.gov/pubmed/36531494 http://dx.doi.org/10.3389/fendo.2022.1042787 |
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