Structural insights into the down-regulation of overexpressed p185(her2/neu) protein of transformed cells by the antibody chA21 |
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Authors: | Zhou Huihao Zha Zhao Liu Yang Zhang Hongtao Zhu Juanjuan Hu Siyi Shen Guodong Cheng Liansheng Niu Liwen Greene Mark I Teng Maikun Liu Jing |
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Affiliation: | School of Life Sciences, Hefei National Laboratory for Physical Sciences at Microscale, Chinese Academy of Sciences, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230027, China. |
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Abstract: | p185(her2/neu) belongs to the ErbB receptor tyrosine kinase family, which has been associated with human breast, ovarian, and lung cancers. Targeted therapies employing ectodomain-specific p185(her2/neu) monoclonal antibodies (mAbs) have demonstrated clinical efficacy for breast cancer. Our previous studies have shown that p185(her2/neu) mAbs are able to disable the kinase activity of homomeric and heteromeric kinase complexes and induce the conversion of the malignant to normal phenotype. We previously developed a chimeric antibody chA21 that specifically inhibits the growth of p185(her2/neu)-overexpressing cancer cells in vitro and in vivo. Herein, we report the crystal structure of the single-chain Fv of chA21 in complex with an N-terminal fragment of p185(her2/neu), which reveals that chA21 binds a region opposite to the dimerization interface, indicating that chA21 does not directly disrupt the dimerization. In contrast, the bivalent chA21 leads to internalization and down-regulation of p185(her2/neu). We propose a structure-based model in which chA21 cross-links two p185(her2/neu) molecules on separate homo- or heterodimers to form a large oligomer in the cell membrane. This model reveals a mechanism for mAbs to drive the receptors into the internalization/degradation path from the inactive hypophosphorylated tetramers formed dynamically by active dimers during a "physiologic process." |
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Keywords: | Antibodies Crystal Structure Protein-Protein Interactions Receptor Endocytosis Tumor Therapy ErbB chA21 Cross-link |
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