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A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-α (TGF-α), to the initiation of intracellular signaling pathways. EGFR binds to EGF and TGF-α with similar affinity, but generates d...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716103/ https://www.ncbi.nlm.nih.gov/pubmed/34846302 http://dx.doi.org/10.7554/eLife.73218 |
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author | Huang, Yongjian Ognjenovic, Jana Karandur, Deepti Miller, Kate Merk, Alan Subramaniam, Sriram Kuriyan, John |
author_facet | Huang, Yongjian Ognjenovic, Jana Karandur, Deepti Miller, Kate Merk, Alan Subramaniam, Sriram Kuriyan, John |
author_sort | Huang, Yongjian |
collection | PubMed |
description | The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-α (TGF-α), to the initiation of intracellular signaling pathways. EGFR binds to EGF and TGF-α with similar affinity, but generates different signals from these ligands. To address the mechanistic basis of this phenomenon, we have carried out cryo-EM analyses of human EGFR bound to EGF and TGF-α. We show that the extracellular module adopts an ensemble of dimeric conformations when bound to either EGF or TGF-α. The two extreme states of this ensemble represent distinct ligand-bound quaternary structures in which the membrane-proximal tips of the extracellular module are either juxtaposed or separated. EGF and TGF-α differ in their ability to maintain the conformation with the membrane-proximal tips of the extracellular module separated, and this conformation is stabilized preferentially by an oncogenic EGFR mutation. Close proximity of the transmembrane helices at the junction with the extracellular module has been associated previously with increased EGFR activity. Our results show how EGFR can couple the binding of different ligands to differential modulation of this proximity, thereby suggesting a molecular mechanism for the generation of ligand-sensitive differential outputs in this receptor family. |
format | Online Article Text |
id | pubmed-8716103 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-87161032022-01-05 A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor Huang, Yongjian Ognjenovic, Jana Karandur, Deepti Miller, Kate Merk, Alan Subramaniam, Sriram Kuriyan, John eLife Biochemistry and Chemical Biology The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-α (TGF-α), to the initiation of intracellular signaling pathways. EGFR binds to EGF and TGF-α with similar affinity, but generates different signals from these ligands. To address the mechanistic basis of this phenomenon, we have carried out cryo-EM analyses of human EGFR bound to EGF and TGF-α. We show that the extracellular module adopts an ensemble of dimeric conformations when bound to either EGF or TGF-α. The two extreme states of this ensemble represent distinct ligand-bound quaternary structures in which the membrane-proximal tips of the extracellular module are either juxtaposed or separated. EGF and TGF-α differ in their ability to maintain the conformation with the membrane-proximal tips of the extracellular module separated, and this conformation is stabilized preferentially by an oncogenic EGFR mutation. Close proximity of the transmembrane helices at the junction with the extracellular module has been associated previously with increased EGFR activity. Our results show how EGFR can couple the binding of different ligands to differential modulation of this proximity, thereby suggesting a molecular mechanism for the generation of ligand-sensitive differential outputs in this receptor family. eLife Sciences Publications, Ltd 2021-11-30 /pmc/articles/PMC8716103/ /pubmed/34846302 http://dx.doi.org/10.7554/eLife.73218 Text en © 2021, Huang et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Huang, Yongjian Ognjenovic, Jana Karandur, Deepti Miller, Kate Merk, Alan Subramaniam, Sriram Kuriyan, John A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor |
title | A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor |
title_full | A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor |
title_fullStr | A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor |
title_full_unstemmed | A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor |
title_short | A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor |
title_sort | molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716103/ https://www.ncbi.nlm.nih.gov/pubmed/34846302 http://dx.doi.org/10.7554/eLife.73218 |
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