title: Simultaneous visualization of the extracellular and cytoplasmic domains of the epidermal growth factor receptor.
abstract: To our knowledge, no structural study to date has characterized, in an intact receptor, the coupling of conformational change in extracellular domains through a single-pass transmembrane domain to conformational change in cytoplasmic domains. Here we examine such coupling, and its unexpected complexity, using nearly full-length epidermal growth factor receptor (EGFR) and negative-stain EM. The liganded, dimeric EGFR ectodomain can couple both to putatively active, asymmetrically associated kinase dimers and to putatively inactive, symmetrically associated kinase dimers and monomers. Inhibitors that stabilize the active or inactive conformation of the kinase active site, as well as mutations in the kinase dimer interface and a juxtamembrane phosphorylation site, shift the equilibrium among the three kinase association states. This coupling of one conformation of an activated receptor ectodomain to multiple kinase-domain arrangements reveals previously unanticipated complexity in transmembrane signaling and facilitates regulation of receptor function in the juxtamembrane and cytoplasmic environments.
authors.affiliation: Immune Disease Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Li-Zhi
authors.initials: LZ
authors.lastname: Mi
authors.forename: Chafen
authors.initials: C
authors.lastname: Lu
authors.forename: Zongli
authors.initials: Z
authors.lastname: Li
authors.forename: Noritaka
authors.initials: N
authors.lastname: Nishida
authors.forename: Thomas
authors.initials: T
authors.lastname: Walz
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D020134:Catalytic Domain; D019281:Dimerization; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D006801:Humans; D008024:Ligands; D009154:Mutation; D017434:Protein Structure, Tertiary
chemical_list: D008024:Ligands; D066246:ErbB Receptors