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Ligand-induced transmembrane conformational coupling in monomeric EGFR

Author

Listed:
  • Shwetha Srinivasan

    (Massachusetts Institute of Technology)

  • Raju Regmi

    (Massachusetts Institute of Technology
    Institut Curie, CNRS, Laboratoire Physico Chimie Curie)

  • Xingcheng Lin

    (Massachusetts Institute of Technology)

  • Courtney A. Dreyer

    (University of California Davis School of Medicine)

  • Xuyan Chen

    (Massachusetts Institute of Technology)

  • Steven D. Quinn

    (Massachusetts Institute of Technology
    University of York)

  • Wei He

    (Lawrence Livermore National Laboratory)

  • Matthew A. Coleman

    (Lawrence Livermore National Laboratory
    University of California Davis School of Medicine)

  • Kermit L. Carraway

    (University of California Davis School of Medicine)

  • Bin Zhang

    (Massachusetts Institute of Technology)

  • Gabriela S. Schlau-Cohen

    (Massachusetts Institute of Technology)

Abstract

Single pass cell surface receptors regulate cellular processes by transmitting ligand-encoded signals across the plasma membrane via changes to their extracellular and intracellular conformations. This transmembrane signaling is generally initiated by ligand binding to the receptors in their monomeric form. While subsequent receptor-receptor interactions are established as key aspects of transmembrane signaling, the contribution of monomeric receptors has been challenging to isolate due to the complexity and ligand-dependence of these interactions. By combining membrane nanodiscs produced with cell-free expression, single-molecule Förster Resonance Energy Transfer measurements, and molecular dynamics simulations, we report that ligand binding induces intracellular conformational changes within monomeric, full-length epidermal growth factor receptor (EGFR). Our observations establish the existence of extracellular/intracellular conformational coupling within a single receptor molecule. We implicate a series of electrostatic interactions in the conformational coupling and find the coupling is inhibited by targeted therapeutics and mutations that also inhibit phosphorylation in cells. Collectively, these results introduce a facile mechanism to link the extracellular and intracellular regions through the single transmembrane helix of monomeric EGFR, and raise the possibility that intramolecular transmembrane conformational changes upon ligand binding are common to single-pass membrane proteins.

Suggested Citation

  • Shwetha Srinivasan & Raju Regmi & Xingcheng Lin & Courtney A. Dreyer & Xuyan Chen & Steven D. Quinn & Wei He & Matthew A. Coleman & Kermit L. Carraway & Bin Zhang & Gabriela S. Schlau-Cohen, 2022. "Ligand-induced transmembrane conformational coupling in monomeric EGFR," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31299-z
    DOI: 10.1038/s41467-022-31299-z
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    References listed on IDEAS

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    1. Inhee Chung & Robert Akita & Richard Vandlen & Derek Toomre & Joseph Schlessinger & Ira Mellman, 2010. "Spatial control of EGF receptor activation by reversible dimerization on living cells," Nature, Nature, vol. 464(7289), pages 783-787, April.
    2. Sarah R. Needham & Selene K. Roberts & Anton Arkhipov & Venkatesh P. Mysore & Christopher J. Tynan & Laura C. Zanetti-Domingues & Eric T. Kim & Valeria Losasso & Dimitrios Korovesis & Michael Hirsch &, 2016. "EGFR oligomerization organizes kinase-active dimers into competent signalling platforms," Nature Communications, Nature, vol. 7(1), pages 1-14, December.
    3. Laura C. Zanetti-Domingues & Dimitrios Korovesis & Sarah R. Needham & Christopher J. Tynan & Shiori Sagawa & Selene K. Roberts & Antonija Kuzmanic & Elena Ortiz-Zapater & Purvi Jain & Rob C. Roovers &, 2018. "The architecture of EGFR’s basal complexes reveals autoinhibition mechanisms in dimers and oligomers," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
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