A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor.

Autor:	Huang Y; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.; Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States.; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States., Ognjenovic J; Frederick National Laboratory for Cancer Research, Frederick, United States., Karandur D; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.; Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States.; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States., Miller K; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States., Merk A; Frederick National Laboratory for Cancer Research, Frederick, United States., Subramaniam S; University of British Columbia, Vancouver, Canada., Kuriyan J; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.; Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States.; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.; Department of Chemistry, University of California, Berkeley, Berkeley, United States.; Divisions of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Nov 30; Vol. 10. Date of Electronic Publication: 2021 Nov 30.
DOI:	10.7554/eLife.73218
Abstrakt:	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. Competing Interests: YH, JO, KM, AM No competing interests declared, DK DK is an early-career reviewer for eLife, SS SS is Founder and Chief Executive Officer of Gandeeva Therapeutics Inc and Reviewing editor, eLife, JK JK is a cofounder of Nurix Therapeutics and is on the scientific advisory boards of Carmot and Revolution Medicine (© 2021, Huang et al.)
Databáze:	MEDLINE
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