2022 journal article
Ligand-induced transmembrane conformational coupling in monomeric EGFR
Nature Communications.
MeSH headings : Cell Membrane / metabolism; ErbB Receptors / metabolism; Ligands; Protein Binding; Protein Conformation
TL;DR:
It is shown that transmembrane conformational coupling is the first step in EGFR signaling, providing evidence for the existence of trans Membrane intramolecular conformational changes in a single pass membrane protein.
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open access via www.nature.com (publisher PDF)
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Source: ORCID
Added: April 5, 2023
AbstractSingle 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.