The EGF receptor binding of recombinant heregulinbeta1/EGF hybrids is blocked by heregulin residue glutamate 195

Biochemical and Biophysical Research Communications
B N ChauS R Campion

Abstract

Defined sequences from the EGF-like domain of human heregulin-beta1 (HRGbeta1) were recombined with a synthetic gene for human epidermal growth factor (hEGF) in an attempt to locate receptor-specific determinants within the HRGbeta1 molecule that blocks its inappropriate association with the EGF receptor (EGFR). Receptor competition assays detected only minor changes in relative EGFR affinity for those hybrids containing up to 12 N-terminal HRGbeta1 residues. However, extending the N-terminal substitution to include 20 HRGbeta1 residues resulted in a 100-fold drop in relative EGFR binding. Both interruption of the major beta-sheet structure of hEGF by insertion of a three amino acid loop present in HRGbeta1 and replacement of nearly the entire C-terminal hEGF subdomain with segments of HRGbeta1 sequence resulted in a 5-fold decreased EGFR affinity. The results presented here demonstrate that while a substantial portion of the hEGF and HRGbeta1 protein sequences were nearly interchangeable with regard to EGFR binding, the introduction of HRGbeta1 residue Glu195 effected a major decrease in EGFR binding.

Citations

Apr 24, 1999·FEBS Letters·J T JonesM X Sliwkowski

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