title: A model for the activation of the epidermal growth factor receptor kinase involvement of an asymmetric dimer?
abstract: The binding of epidermal growth factor (EGF) to its receptor leads to receptor dimerization, which activates the intracellular kinase domain. Homology models of the inactive and active forms of the EGF-receptor kinase domains have been derived, and these models suggest that the active form can be stabilized by the interaction of helix C and the surrounding area in one receptor monomer with one of two possible complementary surfaces on a second receptor monomer. Both hydrophobic interaction sites are strongly conserved within the EGF-receptor family but not in other tyrosine kinases. Two of the three predicted kinase dimers are symmetric; the other is asymmetric and is predicted to contain only one active kinase. One of the symmetric models and the asymmetric model would account for the effects of two mutations in helix C (Y740F and V741G) on kinase activity. They also provide an explanation for previously reported dominant negative mutants of the EGF receptor and have interesting implications for the signaling through homo- and heterodimers of the family members: EGF receptor, erbB2, erbB3, and erbB4.
authors.affiliation: Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia. groenen@ludwig.edu.au
authors.forename: L C
authors.initials: LC
authors.lastname: Groenen
authors.forename: F
authors.initials: F
authors.lastname: Walker
authors.forename: A W
authors.initials: AW
authors.lastname: Burgess
authors.forename: H R
authors.initials: HR
authors.lastname: Treutlein
mesh_terms: D000595:Amino Acid Sequence; D019281:Dimerization; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors