title: Conformational coupling across the plasma membrane in activation of the EGF receptor.
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.
authors: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors: Nicholas F
authors: NF
authors: Endres
authors: Rahul
authors: R
authors: Das
authors: Adam W
authors: AW
authors: Smith
authors: Anton
authors: A
authors: Arkhipov
authors: Erika
authors: E
authors: Kovacs
authors: Yongjian
authors: Y
authors: Huang
authors: Jeffrey G
authors: JG
authors: Pelton
authors: Yibing
authors: Y
authors: Shan
authors: David E
authors: DE
authors: Shaw
authors: David E
authors: DE
authors: Wemmer
authors: Jay T
authors: JT
authors: Groves
authors: John
authors: J
authors: Kuriyan
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D002522:Chlorocebus aethiops; D019281:Dimerization; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015398:Signal Transduction
chemical_list: D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors
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