Conformational coupling across the plasma membrane in activation of the EGF receptor

Cell. 2013 Jan 31;152(3):543-56. doi: 10.1016/j.cell.2012.12.032.

Abstract

How the epidermal growth factor receptor (EGFR) activates is incompletely understood. The intracellular portion of the receptor is intrinsically active in solution, and to study its regulation, we measured autophosphorylation as a function of EGFR surface density in cells. Without EGF, intact EGFR escapes inhibition only at high surface densities. Although the transmembrane helix and the intracellular module together suffice for constitutive activity even at low densities, the intracellular module is inactivated when tethered on its own to the plasma membrane, and fluorescence cross-correlation shows that it fails to dimerize. NMR and functional data indicate that activation requires an N-terminal interaction between the transmembrane helices, which promotes an antiparallel interaction between juxtamembrane segments and release of inhibition by the membrane. We conclude that EGF binding removes steric constraints in the extracellular module, promoting activation through N-terminal association of the transmembrane helices.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • COS Cells
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism*
  • Chlorocebus aethiops
  • Dimerization
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors / chemistry*
  • ErbB Receptors / metabolism
  • Humans
  • Models, Molecular
  • Signal Transduction*

Substances

  • Epidermal Growth Factor
  • EGFR protein, human
  • ErbB Receptors