Architecture and Membrane Interactions of the EGF Receptor

• Published in: Cell 2013-01, Vol.152 (3), p.557-569
• Main Authors: Arkhipov, Anton, Shan, Yibing, Das, Rahul, Endres, Nicholas F., Eastwood, Michael P., Wemmer, David E., Kuriyan, John, Shaw, David E.
• Format: Article
• Language: English
• Subjects: Cell Membrane - chemistry; Cell Membrane - metabolism; Dimerization; dissociation; electrostatic interactions; Epidermal growth factor; epidermal growth factor receptors; ErbB Receptors - chemistry; ErbB Receptors - metabolism; Humans; ligands; Membrane Lipids - metabolism; membranes; molecular dynamics; Molecular Dynamics Simulation; Nuclear Magnetic Resonance, Biomolecular; Protein Conformation; Protein Structure, Tertiary; Static Electricity
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.12.030

Dimerization-driven activation of the intracellular kinase domains of the epidermal growth factor receptor (EGFR) upon extracellular ligand binding is crucial to cellular pathways regulating proliferation, migration, and differentiation. Inactive EGFR can exist as both monomers and dimers, suggesting that the mechanism regulating EGFR activity may be subtle. The membrane itself may play a role but creates substantial difficulties for structural studies. Our molecular dynamics simulations of membrane-embedded EGFR suggest that, in ligand-bound dimers, the extracellular domains assume conformations favoring dimerization of the transmembrane helices near their N termini, dimerization of the juxtamembrane segments, and formation of asymmetric (active) kinase dimers. In ligand-free dimers, by holding apart the N termini of the transmembrane helices, the extracellular domains instead favor C-terminal dimerization of the transmembrane helices, juxtamembrane segment dissociation and membrane burial, and formation of symmetric (inactive) kinase dimers. Electrostatic interactions of EGFR’s intracellular module with the membrane are critical in maintaining this coupling. [Display omitted] ► Full-length EGFRs are modeled in a realistic membrane environment ► The models show how EGF binding controls the extracellular domains in EGFR dimers ► The trans- and juxtamembrane segments alternate between two dimer forms as a result ► Anionic lipids in the membrane are critical to the regulation of the kinase domains Atomistic models of full-length EGFR based on computer simulations illustrate the conformational coupling between the extra- and intracellular components and show that the receptor’s interactions with the anionic lipids in the inner leaflet of the cell membrane are critical to its regulation.