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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...

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Autores principales: Huang, Yongjian, Ognjenovic, Jana, Karandur, Deepti, Miller, Kate, Merk, Alan, Subramaniam, Sriram, Kuriyan, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
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.
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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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