title: Structural evidence for loose linkage between ligand binding and kinase activation in the epidermal growth factor receptor.
abstract: The mechanisms by which signals are transmitted across the plasma membrane to regulate signaling are largely unknown for receptors with single-pass transmembrane domains such as the epidermal growth factor receptor (EGFR). A crystal structure of the extracellular domain of EGFR dimerized by epidermal growth factor (EGF) reveals the extended, rod-like domain IV and a small, hydrophobic domain IV interface compatible with flexibility. The crystal structure and disulfide cross-linking suggest that the 7-residue linker between the extracellular and transmembrane domains is flexible. Disulfide cross-linking of the transmembrane domain shows that EGF stimulates only moderate association in the first two α-helical turns, in contrast to association throughout the membrane over five α-helical turns in glycophorin A and integrin. Furthermore, systematic mutagenesis to leucine and phenylalanine suggests that no specific transmembrane interfaces are required for EGFR kinase activation. These results suggest that linkage between ligand-induced dimerization and tyrosine kinase activation is much looser than was previously envisioned.
authors.affiliation: Immune Disease Institute and Department of Pathology, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02115, USA.
authors.forename: Chafen
authors.initials: C
authors.lastname: Lu
authors.forename: Li-Zhi
authors.initials: LZ
authors.lastname: Mi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Grey
authors.forename: Jieqing
authors.initials: J
authors.lastname: Zhu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Graef
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000737:chemistry; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D014961:X-Ray Diffraction
chemical_list: D003432:Cross-Linking Reagents; D004220:Disulfides; D008024:Ligands; D066246:ErbB Receptors; D003545:Cysteine