Human Epidermal growth factor Receptor 4 (HER4 or ERBB4) carries out essential functions in the development and maintenance of the cardiovascular and nervous systems. HER4 activation is regulated by a diverse group of extracellular ligands including the neuregulin (NRG) family and betacellulin (BTC), which promote HER4 homodimerization or heterodimerization with other HER receptors. Important cardiovascular functions of HER4 are exerted via heterodimerization with its close homolog and orphan receptor, HER2. To date structural insights into ligand-mediated HER4 activation have been limited to crystallographic studies of HER4 ectodomain homodimers in complex with NRG1β. Here, we report cryo-EM structures of near full-length HER2/HER4 heterodimers and full-length HER4 homodimers bound to NRG1β and BTC. We show that the structures of the heterodimers bound to either ligand are nearly identical and that in both cases the HER2/HER4 heterodimer interface is less dynamic than those observed in structures of HER2/EGFR and HER2/HER3 heterodimers. In contrast, structures of full-length HER4 homodimers bound to NRG1β and BTC display more large-scale dynamics mirroring states previously reported for EGFR homodimers. Our structures also reveal the presence of multiple glycan modifications within HER4 ectodomains, modeled for the first time in HER receptors, that distinctively contribute to the stabilization of HER4 homodimer interfaces over those of HER2/HER4 heterodimers.

中文翻译：

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活性 HER4 和 HER2/HER4 复合物的结构动力学通过不同的生长因子和糖基化进行微调

人表皮生长因子受体 4（HER4 或 ERBB4）在心血管和神经系统的发育和维护中发挥重要作用。HER4 激活受到多种细胞外配体的调节，包括神经调节蛋白 (NRG) 家族和 betacellulin (BTC)，它们促进 HER4 与其他 HER 受体的同二聚化或异二聚化。HER4 的重要心血管功能是通过与其密切同源物和孤儿受体 HER2 的异二聚化发挥的。迄今为止，对配体介导的 HER4 激活的结构了解仅限于与 NRG1β 复合的 HER4 胞外域同二聚体的晶体学研究。在这里，我们报告了与 NRG1β 和 BTC 结合的近全长 HER2/HER4 异二聚体和全长 HER4 同二聚体的冷冻电镜结构。我们表明，与任一配体结合的异二聚体的结构几乎相同，并且在这两种情况下，HER2/HER4 异二聚体界面的动态性低于 HER2/EGFR 和 HER2/HER3 异二聚体结构中观察到的动态。相比之下，与NRG1β和BTC结合的全长HER4同型二聚体的结构显示出更大规模的动态镜像状态，此前报道的EGFR同型二聚体。我们的结构还揭示了 HER4 胞外域内存在多种聚糖修饰，这是首次在 HER 受体中建模，与 HER2/HER4 异二聚体相比，这些修饰对 HER4 同二聚体界面的稳定做出了独特贡献。