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

  1. Yongjian Huang
  2. Jana Ognjenovic
  3. Deepti Karandur
  4. Kate Miller
  5. Alan Merk
  6. Sriram Subramaniam  Is a corresponding author
  7. John Kuriyan  Is a corresponding author
  1. University of California, Berkeley, United States
  2. Frederick National Laboratory for Cancer Research, United States
  3. Howard Hughes Medical Institute, University of California, Berkeley, United States
  4. 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.

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Article and author information

Author details

  1. Yongjian Huang

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  2. Jana Ognjenovic

    Frederick National Laboratory for Cancer Research, Frederick, United States
    Competing interests
    No competing interests declared.
  3. Deepti Karandur

    Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    Deepti Karandur, D.K. is an early-career reviewer for eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6949-6337
  4. Kate Miller

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  5. Alan Merk

    Frederick National Laboratory for Cancer Research, Frederick, United States
    Competing interests
    No competing interests declared.
  6. Sriram Subramaniam

    Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
    For correspondence
    Sriram.Subramaniam@ubc.ca
    Competing interests
    Sriram Subramaniam, S.S. is Founder and Chief Executive Officer of Gandeeva Therapeutics Inc.Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4231-4115
  7. John Kuriyan

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    jkuriyan@mac.com
    Competing interests
    John Kuriyan, J.K. is a cofounder of Nurix Therapeutics and is on the scientific advisory boards of Carmot and Revolution Medicine..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4414-5477

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.

Reviewing Editor

  1. Mingjie Zhang, Hong Kong University of Science and Technology, Hong Kong

Publication history

  1. Preprint posted: December 9, 2020 (view preprint)
  2. Received: August 20, 2021
  3. Accepted: November 19, 2021
  4. Accepted Manuscript published: November 30, 2021 (version 1)
  5. Version of Record published: December 24, 2021 (version 2)

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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  1. Yongjian Huang
  2. Jana Ognjenovic
  3. Deepti Karandur
  4. Kate Miller
  5. Alan Merk
  6. Sriram Subramaniam
  7. John Kuriyan
(2021)
A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor
eLife 10:e73218.
https://doi.org/10.7554/eLife.73218

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