Molecular Architecture Of HER2 Homodimer

Human epidermal growth factor receptor(EGFR) superfamily play significant roles in in numerous cellular processes. There are four members in this superfamily, one is the well-know receptor EGFR. Among them, Human epidermal growth factor receptor II(HER2) has been the research hotspot in oncology and tumor therapy studies recently. Overexpression, aberrant activation and somatic mutation of HER2 has been reported among breast cancer, gastric cancer, lung cancer, ovarian cancer and prostate cancers. In breast cancer, HER2 has been identified as an independent rognostic marker and aroused widespread enthusiasm. In the field of targeted therapy for treating breast cancer and gastric cancer, anti-HER2 antibodies and small molecule tyrosine kinase inhibitors have beome the backbone of combination therapy with current chemotherapy and radiotherapy in clinic.HER2 belongs to the type I transmembrane receptor tyrosine kinases with a molecular weight of 180 KDa. The intracellular tyrosine kinase activity of HER2 is stronger than other family members. Compared with other family members, HER2 has the following features: 1) the specific soluble ligand for HER2 has not yet been identified. 2) HER2 is the preferred dimerization partner in the dimerization patterm amony the family. 3) Privous crystal structure reported has showed that HER2 do not have the structural shift between a ‘tethered’ intramolecular conformation to the dimerization-competent conformation but a in the activated state. However, the molecular mechanism of the dimerization of ErbB2 remains elusive, intellectual dispute has been aroused for the activation and dimierzation model of HER2 and it is obviously not reasonable to use the EGFR dimerization model as the molecular mechanism for the dimerization of all the members.In this paper, we firest reported crystal structures of three HER2/Fab complexes, of which these antibodies did not affect the homodimerization of HER2. The three structure of HER2/Fab complexes were sovled to 3.3 ?, 3.5 ? and 3.1 ?. Next, we successfully solved the phase problem of the three structures of three HER2/Fab complexes by molecular replacement method. Carefully structural analysis of the three HER2/Fab complex hint a HER2 homodimerizaiton interaction/ molecular architecture. Based on the strutural analysis, mutagenesis study, cell membrane surface proterin crosslinking assays, co-immunoprecipitation assays, and phosphorylation assays, we revealed the molecular architecture of the HER2 homodimer. Moreover, we also elucidated the different impacts and molecular basis for therapeutic antibodies on ErbB2 dimerization.In the last, based on the thorough analysis of the EGFR homodimer model and HER2 homodimer model, we confimed a novel dimerziaon basis for the EGFR members: the “back to head” dimerization pattern. This molecular architecture was the basis for the study of dimerization of EGFR family receptors and make challenges to the traditional point of view. All in all, this work has important significance for understanding the physiological processes of dimerization of HER2 and the EGFR family receptors.