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. 1994 Aug 1;13(15):3517–3523. doi: 10.1002/j.1460-2075.1994.tb06658.x

Solution structure of the epidermal growth factor-like domain of heregulin-alpha, a ligand for p180erbB-4.

K Nagata 1, D Kohda 1, H Hatanaka 1, S Ichikawa 1, S Matsuda 1, T Yamamoto 1, A Suzuki 1, F Inagaki 1
PMCID: PMC395255  PMID: 8062828

Abstract

p185erbB-2 and p180erbB-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 p180erbB-4 and activate p180erbB-4 and p185erbB-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 p180erbB-4 ligands (HRGs) and the p170erbB-1 ligands [EGF and transforming growth factor (TGF)-alpha]. To investigate the structural basis of receptor specificity, we have determined the solution structure of the EGF-like domain of HRG-alpha 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-alpha, distinctive structural features are observed on the molecular surface including an ionic cluster and hydrophobic patches, which afford HRG-alpha the specific affinity for p180erbB-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.

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Selected References

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