A Model for the Activation of the Epidermal Growth Factor Receptor Kinase:  Involvement of an Asymmetric Dimer?

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 st...

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Bibliographic Details
Published in:Biochemistry (Easton) 1997-04, Vol.36 (13), p.3826-3836
Main Authors: Groenen, Leo C, Walker, Francesca, Burgess, Antony W, Treutlein, Herbert R
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Dimerization
Enzyme Activation
Epidermal Growth Factor - metabolism
Humans
Models, Molecular
Molecular Sequence Data
Mutation - genetics
Phosphorylation
Protein Binding
Protein Conformation
Protein Folding
Protein Structure, Secondary
Receptor, Epidermal Growth Factor - chemistry
Receptor, Epidermal Growth Factor - metabolism
Sequence Alignment
Sequence Homology, Amino Acid
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Summary: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.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi9614141