SOLUTION STRUCTURE OF THE EPIDERMAL GROWTH FACTOR-LIKE DOMAIN OF HEREGULIN-ALPHA, A LIGAND FOR P180(ERBB-4)

被引:51
作者
NAGATA, K
KOHDA, D
HATANAKA, H
ICHIKAWA, S
MATSUDA, S
YAMAMOTO, T
SUZUKI, A
INAGAKI, F
机构
[1] TOKYO METROPOLITAN INST MED SCI,DEPT MOLEC PHYSIOL,BUNKYO KU,TOKYO 113,JAPAN
[2] UNIV TOKYO,FAC AGR,DEPT AGR CHEM,BUNKYO KU,TOKYO 113,JAPAN
[3] UNIV TOKYO,INST MED SCI,DEPT ONCOL,MINATO KU,TOKYO 108,JAPAN
关键词
EPIDERMAL GROWTH FACTOR-LIKE DOMAIN; HEREGULIN; NUCLEAR MAGNETIC RESONANCE STRUCTURE; PL80(ERBB-4); RECEPTOR RECOGNITION;
D O I
10.1002/j.1460-2075.1994.tb06658.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
p185(erbB-2) and p180(erbB-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(erbB-4) and activate p180(erbB-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)-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 H-1 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 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.
引用
收藏
页码:3517 / 3523
页数:7
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