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PMID: 8062828 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The EMBO journal ·Vol. 13 ·No. 15 ·1994-08-01 ·Pages 3517-23

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

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.

MeSH Terms
Amino Acid Sequence Computer Graphics Epidermal Growth Factor/chemistry ErbB Receptors/metabolism Glycoproteins/chemistry,metabolism Ligands Magnetic Resonance Spectroscopy Models, Molecular Molecular Sequence Data Molecular Structure Neuregulins Protein Structure, Secondary Protein Structure, Tertiary Receptor, ErbB-4 Sequence Alignment Transforming Growth Factor alpha/chemistry
Chemicals
Glycoproteins Ligands Neuregulins Transforming Growth Factor alpha Epidermal Growth Factor ErbB Receptors Receptor, ErbB-4
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Nagata K
Department of Molecular Physiology, Tokyo Metropolitan Institute of Medical Science, Japan.
Kohda D
Hatanaka H
Ichikawa S
Matsuda S
Yamamoto T
Suzuki A
Inagaki F
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1994-08-01
Pages
3517-23
Language
English
Region
England
NLM ID
8208664
PMCID
PMC395255
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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