Membrane proteins regulate several vital cellular processes, establishing them as major drug targets. A main function of membrane proteins is to transduce extracellular signal across the membrane bilayer. One such protein is the epidermal growth factor receptor (EGFR), which plays a crucial role in cell signaling and is implicated in cancer. While the structures of the extracellular and intracellular regions of this protein have been well-elucidated individually, conformational coupling connecting these two regions during signal transduction is challenging to probe due to the mixture of hydrophobic and hydrophilic domains intrinsic to membrane proteins. Here, I will discuss the signal transduction mechanism across full-length EGFR. We combine two biochemical tools, cell-free protein expression and nanodiscs, to isolate full-length, functional EGFR in a near-physiological environment. Using a multidisciplinary approach involving single-molecule Förster resonance energy transfer, mutagenesis, and molecular dynamics simulations, we observe a compaction in the intracellular domain of EGFR upon extracellular ligand binding in a neutral lipid environment. The ligand-induced extracellular/intracellular conformational coupling is reversed in the presence of anionic lipids and is robust around the physiological 15-30% anionic content. Our findings show how the extracellular and intracellular domains are coupled to each other in this critical receptor and the impact of the lipid composition in this conformational coupling. Our results could be universal to other membrane receptors which share the same structural homology and perform other significant functions.

Conformational coupling across the membrane bilayer of full-length epidermal growth factor receptor

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ACS Fall 2022

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