Molecular architecture of the ErbB2 extracellular domain homodimer
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Shi Hu1,2,3,4,*, Yuna Sun2,3,*, Yanchun Meng5,6,7,*, Xiaoze Wang5, Weili Yang4,5, Wenyan Fu4, Huaizu Guo1,6, Weizhu Qian1,6, Sheng Hou1,4,6,7, Bohua Li1,4, Zihe Rao2,3, Zhiyong Lou3, Yajun Guo1,4,5,6,7
1International Joint Cancer Institute & Translational Medicine Research Institute, the Second Military Medical University, Shanghai, 200433, P.R. China
2National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, 100101, P.R. China
3Laboratory of Structural Biology and MOE Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, 100084, P.R. China
4Cancer Center, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, 100853, P.R. China
5School of Medicine, Nankai University, Tianjin, 300071, P.R. China
6National Engineering Research Center for Antibody Medicine and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai, 201203, P.R. China
7School of Pharmacy, Liaocheng University, Liaocheng, Shandong, 252000, P.R. China
*These authors have contributed equally to this work
Yajun Guo, e-mail: [email protected]
Zhiyong Lou, e-mail: [email protected]
Keywords: ErbB2, dimerization, signal transduction, crystal structure, Oncogene
Received: October 08, 2014 Accepted: November 08, 2014 Published: January 30, 2015
Human epidermal growth factor receptors (HERs or ErbBs) play crucial roles in numerous cellular processes. ErbB2 is a key member of ErbB family, and its overexpression is recognized as a frequent molecular abnormality. In cancer, this overexpression correlates with aggressive disease and poor patient outcomes. Dimer-dependent phosphorylation is a key event for the signal transduction of ErbBs. However, the molecular mechanism of the dimerization of ErbB2 remains elusive. In the present work, we report the homodimer architecture of the ErbB2 extracellular domain (ECD) which is unique compared with other dimer-models of ErbBs. The structure of the ErbB2 ECD homodimer represents a “back to head” interaction, in which a protruding β-hairpin arm in domain II of one ErbB2 protomer is inserted into a C-shaped pocket created by domains I–III of the adjacent ErbB2 protomer. This dimerized architecture and its impact on the phosphorylation of ErbB2 intracellular domain were further verified by a mutagenesis study. We also elucidated the different impacts of two clinically administered therapeutic antibodies, trastuzumab and pertuzumab, on ErbB2 dimerization. This information not only provides an understanding of the molecular mechanism of ErbBs dimerization but also elucidates ErbB2-targeted therapy at the molecular level.
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