Ligand-induced transmembrane conformational coupling in monomeric EGFR

Shwetha Srinivasan, Raju Regmi, Xingcheng Lin, Courtney A. Dreyer, Xuyan Chen, Steven D. Quinn, Wei He, Matthew A. Coleman, Kermit L. Carraway, Bin Zhang () and Gabriela S. Schlau-Cohen ()
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Shwetha Srinivasan: Massachusetts Institute of Technology
Raju Regmi: Massachusetts Institute of Technology
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
Wei He: Lawrence Livermore National Laboratory
Matthew A. Coleman: Lawrence Livermore National Laboratory
Kermit L. Carraway: University of California Davis School of Medicine
Bin Zhang: Massachusetts Institute of Technology
Gabriela S. Schlau-Cohen: Massachusetts Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31299-z

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