A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor
- University of California, Berkeley, United States
- Frederick National Laboratory for Cancer Research, United States
- Howard Hughes Medical Institute, University of California, Berkeley, United States
- University of British Columbia, Canada
Abstract
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.
Data availability
Human EGFR protein sequence is available from UniProt accession no. P00533. The cryo-EM density maps of EGFR(WT):EGF complex in juxtaposed and separated conformations, EGFR(WT):TGF-a complex in juxtaposed and separated conformations, EGFR(L834R):EGF complex in juxtaposed and separated conformations, have been deposited to the Electron Microscopy Data Bank (EMDB) under the accession codes EMD-25522 and EMD-25523, EMD-25563 and EMD-25561, EMD-25558 and EMD-25559, respectively. The associated coordinates have been deposited to the PDB under accession codes 7SYD and 7SYE, 7SZ7 and 7SZ5, 7SZ0 and 7SZ1, respectively.
Article and author information
Author details
Sriram Subramaniam
Funding
Canada Excellence Research Chairs, Government of Canada
- Sriram Subramaniam
VGH and UBC Hospital Foundation
- Sriram Subramaniam
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Huang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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