Cell
Volume 152, Issue 3, 31 January 2013, Pages 543-556
Journal home page for Cell

Article
Conformational Coupling across the Plasma Membrane in Activation of the EGF Receptor

https://doi.org/10.1016/j.cell.2012.12.032Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Highlights

► Interactions with the membrane help suppress ligand-independent EGFR activation ► Dependence of EGFR activation on cell surface density reveals control mechanisms ► Intrinsic dimerization of the cytoplasmic module is suppressed at the membrane ► Activation requires structural coupling of transmembrane and juxtamembrane segments

Cited by (0)

9

These authors contributed equally to this work

10

Present address: Department of Chemistry, University of Akron, Akron, OH 44325, USA