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J Biol Chem, Vol. 273, Issue 19, 11675-11684, May 8, 1998
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From the Departments of Heregulins (HRGs) are epidermal growth factor
(egf) domain containing polypeptide growth factors that
bind and activate several members of the ErbB receptor family. Although
HRG can bind to ErbB3 and ErbB4 homodimers, the highest affinity and
most intracellularly active receptor complexes are hetero-oligomers
containing ErbB2. The HRG Protein Engineering and
¶ Protein Chemistry, Genentech, Incorporated,
South San Francisco, California 94080
egf domain was displayed on
the surface of M13 phage to facilitate mutagenic analysis and optimize
for binding to a homodimeric ErbB3-immunoglobulin (IgG) fusion. Nine
libraries were constructed in which virtually the entire sequence was
randomized in stretches of four to six amino acids. These were selected
separately for binding to immobilized ErbB3-IgG. Analysis of the
resulting sequences revealed some areas that diverged radically from
the wild-type, whereas others showed strong conservation. The degree of
wild-type conservation correlated strongly with the functional importance of the residues as determined by alanine scanning
mutagenesis (Jones, J. T., Ballinger, M. D., Pisacane,
P. I., Lofgren, J. A., Fitzpatrick, V. D., Fairbrother,
W. J., Wells, J. A., and Sliwkowski, M. X. (1998)
J. Biol. Chem. 273, 11667-11674). Some variants from
several libraries showed significant improvements in binding affinity
to the ErbB3-IgG. These optimized segments were combined in various
ways in the same molecule to generate variants (containing up to 16 mutations) that had >50-fold higher affinity than wild-type HRG.
The optimized variants stimulated ErbB2 phophorylation on MCF7 cells at
levels similar to wild-type. This indicates wild-type affinity is
optimized for potency and that factors other than affinity for ErbB3
are limiting. These variants showed enhanced affinity toward the ErbB4
homodimer, suggesting these receptors use very similar binding
determinants despite them having 65% sequence identity.
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