Structural analysis of a EGF/TGFα chimera with
unique Erbβ binding specificity
Various chimeras of the ErbB1 specific ligands EGF
and TGFa display a much enlarged repertoire as activators
of ErbB2•ErbB3 heterodimers. Mutational analysis
indicated that particularly residues in the N-terminus and
B-loop region are involved in the broadened receptor
specificity. To study a possible correlation between ligand
structure and ErbB binding specificity, we determined the
solution structure of T1E, a chimeric ligand constructed by
introduction of the N-terminus of TGFa into EGF. The
results showed that the overall structural fold of T1E in
solution is very similar to that of EGF and TGFa,
consisting of a major and a minor antiparallel b-sheet,
held together by three disulfide bridges. However, the
N-terminus of T1E shows an extended structure which is
appropriately positioned to form a triple b-sheet with the
large antiparallel b-sheet in the B-loop region. Evaluation
of backbone 15N NMR relaxation parameters showed that T1E
is a relatively flexible molecule. Based on the T1E NMR
structure and the known crystal structures of ErbB3 and the
EGF•ErbB1 and TGFa•ErbB1 complexes, superposition
models were generated for T1E binding to both the
ErbB1-domain I and ErbB3-domain I. These models provided
for a structural interpretation of the broadened ErbB
specificity of this EGF/ TGFa chimera.
PDB code 1PGJ. (
Download)
■ Wingens, M.,
Walma, T., van Ingen, H., Stortelers, C., van Leeuwen,
J.E.M., van Zoelen, E.J.J. & Vuister, G.W. (2003)
“Structural analysis of an EGF/TGFa chimera with
unique ERBb binding specificity”,
J. Biol.
Chem. 278, 39114-39123.
