HER2属于人类表皮生长因子受体酪氨酸激酶家族。其过度表达或过度活化是多种癌症的主要原因。 HER2主要通过与其他家族成员（例如EGFR）二聚化进行功能。然而，异二聚体组装的分子细节尚未完全理解。在这里，我们报告了EGF和表皮生长因子结合的EGFR / HER2外域复合物的冷冻电镜结构，分别以3.3 Å和4.5 Å的分辨率。结合功能分析，我们证明仅HER2的二聚化臂，而非EGFR的二聚化臂，对于它们的异二聚体形成和信号转导是必不可少的。此外，我们使用单分子实时细胞成像分析了基因组编辑细胞中内源性EGFR和HER2分子的差异膜动力学和瞬态相互作用。此外，我们还展示了与HER2的相互作用可以使EGFR抵抗内吞作用。综上，这项工作深入了解EGFR / HER2复合物的独特结构特性和动力学。 © 2023.作者(们)。

HER2 belongs to the human epidermal growth factor receptor tyrosine kinase family. Its overexpression or hyperactivation is a leading cause for multiple types of cancers. HER2 functions mainly through dimerization with other family members, such as EGFR. However, the molecular details for heterodimer assembly have not been completely understood. Here, we report cryo-EM structures of the EGF- and epiregulin-bound EGFR/HER2 ectodomain complexes at resolutions of 3.3 Å and 4.5 Å, respectively. Together with the functional analyses, we demonstrate that only the dimerization arm of HER2, but not that of EGFR, is essential for their heterodimer formation and signal transduction. Moreover, we analyze the differential membrane dynamics and transient interactions of endogenous EGFR and HER2 molecules in genome-edited cells using single-molecule live-cell imaging. Furthermore, we show that the interaction with HER2 could allow EGFR to resist endocytosis. Together, this work deepens our understanding of the unique structural properties and dynamics of the EGFR/HER2 complex.© 2023. The Author(s).