Single EGF mutants unravel the mechanism for stabilization of Epidermal Growth Factor Receptor (EGFR) system

Abstract

The Epidermal Growth Factor Receptor (EGFR) is a membrane-anchored tyrosine kinase that is able to respond to multiple extra-cellular stimuli in a selective way. Previous studies have pointed out that the modularity of this system could be carried out by ligand-induced differences in the stability of the dimerized receptor. However, nobody has ever explored this hypothesis by observing the effects of single-mutant ligands so far.

Herein, we generated single mutants after we identified positions responsible of inducing functional divergence among paralog ligands using a newly developed approach. Then, we assessed the mutants’ effects on the receptor by employing a combination of molecular dynamics and experimental techniques. Although having comparable binding affinities for EGFR to the wild type, the mutants induced different responses at both the receptor and the cellular level. This study shows for the first time that a functional transition in EGFR can be imparted with as little as one targeted mutation on the ligand. These results also support the theory of biased signaling in the tyrosine kinase receptor system.