title: Human epidermal growth factor receptor (HER1) aligned on the plasma membrane adopts key features of Drosophila EGFR asymmetry.
abstract: Current models suggest that ligand-binding heterogeneity in HER1 [human EGFR (epidermal growth factor receptor] arises from negative co-operativity in signalling HER1 dimers, for which the asymmetry of the extracellular region of the Drosophila EGFR has recently provided a structural basis. However, no asymmetry is apparent in the current crystal structure of the isolated extracellular region of HER1. This receptor also differs from the Drosophila EGFR in that negative co-operativity is found only in full-length receptors in cells. Structural insights into HER1 in epithelial cells, derived from FLIM (fluorescence lifetime imaging microscopy) and two-dimensional FRET (Förster resonance energy transfer) combined with Monte Carlo and molecular dynamics simulations, have demonstrated a high-affinity ligand-binding HER1 conformation consistent with the extracellular region aligned flat on the plasma membrane. This conformation shares key features with that of the Drosophila EGFR, suggesting that the structural basis for negative co-operativity is conserved from invertebrates to humans, but that, in HER1, the extracellular region asymmetry requires interactions with the plasma membrane.
authors.affiliation: Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council Rutherford Appleton Laboratory, Didcot, Oxon OX11 0QX, UK. marisa.martin-fernandez@stfc.ac.uk
authors.forename: Marisa L
authors.initials: ML
authors.lastname: Martin-Fernandez
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000502:physiology*; D029721:Drosophila Proteins / Q000737:chemistry / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000737:chemistry; D066246:ErbB Receptors / Q000737:chemistry / Q000502:physiology*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D018010:Receptors, Invertebrate Peptide / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D029721:Drosophila Proteins; D018010:Receptors, Invertebrate Peptide; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; C066532:Egfr protein, Drosophila; D066246:ErbB Receptors