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Solution structure of the epidermal growth factor‐like domain of heregulin‐alpha, a ligand for p180erbB‐4.
Author(s) -
Nagata K.,
Kohda D.,
Hatanaka H.,
Ichikawa S.,
Matsuda S.,
Yamamoto T.,
Suzuki A.,
Inagaki F.
Publication year - 1994
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/j.1460-2075.1994.tb06658.x
Subject(s) - metropolitan area , library science , physiology , biology , medicine , computer science , pathology
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.