Solution structure of the epidermal growth factor-like domain of heregulin-alpha, a ligand for p180erbB-4.
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.
Nagata
K
K
Department of Molecular Physiology, Tokyo Metropolitan Institute of Medical Science, Japan.
Kohda
D
D
Hatanaka
H
H
Ichikawa
S
S
Matsuda
S
S
Yamamoto
T
T
Suzuki
A
A
Inagaki
F
F
D000595:Amino Acid Sequence; D003196:Computer Graphics; D004815:Epidermal Growth Factor / Q000737:chemistry; D066246:ErbB Receptors / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D020880:Neuregulins; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D066247:Receptor, ErbB-4; D016415:Sequence Alignment; D016211:Transforming Growth Factor alpha / Q000737:chemistry
D006023:Glycoproteins; D008024:Ligands; D020880:Neuregulins; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D066247:Receptor, ErbB-4