Activation of the epidermal growth factor receptor: a series of twists and turns.
The cell surface epidermal growth factor receptor (EGFR) plays a critical role in cell development and oncogenesis. The binding of growth factors to the EGFR results in a mechanical signal being transmitted through the plasma membrane. In this study, atomistic molecular dynamics simulations have been used to investigate the conformational changes associated with the binding of the epidermal growth factor (EGF) and transforming growth factor α (TGFα) to the EGFR. In the simulations, the removal of the EGF and TGFα from the extracellular domain of the EGFR homodimer led to a relative rotation of the protomers of 16-35° about the dimerization axis. The three N-terminal domains that make up the extracellular region of the receptor undergo essentially rigid-body motion. The dimerization interface itself was found to be largely unaffected by the removal of the ligand. In most simulations, the rotation within the dimer was associated with an opening of the cytokine-binding sites. On the basis of these simulations, a simple mechanical model that explains the coupling between the binding of ligand and the motions in the extracellular domains is proposed.
School of Chemistry and Molecular Biosciences, The University of Queensland , Brisbane, QLD 4072, Australia.
David
D
Poger
Alan E
AE
Mark
D001665:Binding Sites; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D055503:Protein Multimerization; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D016211:Transforming Growth Factor alpha / Q000378:metabolism*
D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors