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Binding of single-mutant epidermal growth factor (EGF) ligands alters the stability of the EGF receptor dimer and promotes growth signaling
https://oist.repo.nii.ac.jp/records/2204
https://oist.repo.nii.ac.jp/records/22048aed71e9-de76-4fd3-9869-ba281b075bb8
名前 / ファイル | ライセンス | アクション |
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Pascarelli-2021-Binding-of-single-mutant-epide (4.3 MB)
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Creative Commons Attribution 4.0 International(https://creativecommons.org/licenses/by/4.0/)
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Item type | 学術雑誌論文 / Journal Article(1) | |||||
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公開日 | 2021-08-25 | |||||
タイトル | ||||||
言語 | en | |||||
タイトル | Binding of single-mutant epidermal growth factor (EGF) ligands alters the stability of the EGF receptor dimer and promotes growth signaling | |||||
言語 | ||||||
言語 | eng | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
資源タイプ | journal article | |||||
著者(英) |
Pascarelli, Stefano
× Pascarelli, Stefano× Merzhakupova, Dalmira× Uechi, Gen-Ichiro× Laurino, Paola |
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書誌情報 |
en : Journal of Biological Chemistry 巻 297, 号 1, p. 100872, 発行日 2021-06-11 |
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抄録 | ||||||
内容記述タイプ | Other | |||||
内容記述 | The epidermal growth factor receptor (EGFR) is a membrane-anchored tyrosine kinase that is able to selectively respond to multiple extracellular stimuli. Previous studies have indicated that the modularity of this system may be caused by ligand-induced differences in the stability of the receptor dimer. However, this hypothesis has not been explored using single-mutant ligands thus far. Herein, we developed a new approach to identify residues responsible for functional divergence by selecting residues in the epidermal growth factor (EGF) ligand that are conserved among orthologs yet divergent between paralogs. Then, we mutated these residues and assessed the mutants' effects on the receptor using a combination of molecular dynamics (MD) and biochemical techniques. Although the EGF mutants had binding affinities for the EGFR comparable with the WT ligand, the EGF mutants showed differential patterns of receptor phosphorylation and cell growth in multiple cell lines. The MD simulations of the EGF mutants indicated that mutations had long-range effects on the receptor dimer interface. This study shows for the first time that a single mutation in the EGF is sufficient to alter the activation of the EGFR signaling pathway at the cellular level. These results also support that biased ligand-receptor signaling in the tyrosine kinase receptor system can lead to differential downstream outcomes and demonstrate a promising new method to study ligand-receptor interactions. | |||||
出版者 | ||||||
出版者 | Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology | |||||
ISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 0021-9258 | |||||
ISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 1083-351X | |||||
PubMed番号 | ||||||
関連タイプ | isIdenticalTo | |||||
識別子タイプ | PMID | |||||
関連識別子 | info:pmid/34126069 | |||||
DOI | ||||||
関連タイプ | isIdenticalTo | |||||
識別子タイプ | DOI | |||||
関連識別子 | info:doi/10.1016/j.jbc.2021.100872 | |||||
権利 | ||||||
権利情報 | © 2021 The Author(s). | |||||
関連サイト | ||||||
識別子タイプ | URI | |||||
関連識別子 | https://www.sciencedirect.com/science/article/pii/S0021925821006724?via%3Dihub | |||||
著者版フラグ | ||||||
出版タイプ | VoR | |||||
出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 |