Solution structure of the epidermal growth factor-like domain of heregulin-α a ligand for p180(erbB-4)

K. Nagata, D. Kohda, H. Hatanaka, S. Ichikawa, S. Matsuda, T. Yamamoto, A. Suzuki, F. Inagaki

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45 Citations (Scopus)

Abstract

p185(erB-2) and p180(erB-4) are epidermal growth factor (EGF) receptor-like tyrosine kinases, whose co-expression is observed in many breast carcinomas. Heregulins (HRGs), which contain an immunoglobulin unit and an EGF-like domain, bind to p180(erB-4) and activate p180(erB-4) and p185(erbB-2) through transphosphorylation or receptor heterodimerization. The EGF-like domain is sufficient for the activation. Despite the sequence similarity, no cross activity is seen between the p180(erbB-4) ligands (HRGs) and the p170(erbB-1) ligands [EGF and transforming growth factor (TGF)-α]. To investigate the structural basis of receptor specificity, we have determined the solution structure of the EGF-like domain of HRG-α by two-dimensional 1H nuclear magnetic resonance spectroscopy and simulated annealing calculations. Though its main-chain fold is similar to those of EGF and TGF-α, distinctive structural features are observed on the molecular surface including an ionic cluster and hydrophobic patches, which afford HRG-α the specific affinity for p180(erbB-4). The structure should provide a basis for the structure - activity relationship of HRGs and for the design of drugs which prevent progression of breast cancer.

Original languageEnglish
Pages (from-to)3517-3523
Number of pages7
JournalEMBO Journal
Volume13
Issue number15
DOIs
Publication statusPublished - 1994
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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