Zinc regulates ERp44-dependent protein quality control in the early secretory pathway
Zinc regulates ERp44-dependent protein quality control in the early secretory pathway
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DOI：
10.1038/s41467-019-08429-1
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发表时间：
2019-02
影响因子：
16.6
通讯作者：
Satoshi Watanabe;Yuta Amagai;S. Sannino;T. Tempio;T. Anelli;M. Harayama;Shoji Masui;Ilaria Sorrentino-Ilaria
中科院分区：
文献类型：
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作者：
Satoshi Watanabe;Yuta Amagai;S. Sannino;T. Tempio;T. Anelli;M. Harayama;Shoji Masui;Ilaria Sorrentino-Ilaria
锌离子（Zn 2+）通过高尔基体转运蛋白进入早期分泌途径，但其处理和功能尚未完全了解。在这里，我们表明，锌离子结合高亲和力的pH敏感的伴侣ERp 44，调节其定位和检索客户端，如Ero 1 α和ERAP 1的内质网（ER）的能力。沉默将Zn 2+摄取到高尔基体中的Zn 2+转运蛋白导致ERp 44功能障碍，并增加Ero 1 α和ERAP 1的分泌。高分辨率的晶体结构的Zn 2+结合ERp 44显示，Zn 2+结合到一个保守的组氨酸簇。随之而来的监管C-末端尾部的大位移暴露底物结合表面和RDEL基序，确保客户端捕获和检索。ERp 44还形成Zn 2+桥接的同源二聚体，其在客户端结合时解离。锌结合位点的组氨酸突变损害ERp 44的活性和定位。我们的研究结果揭示了锌离子的作用作为一个关键的调节蛋白质的质量控制在ER-高尔基体接口。
Zinc ions (Zn2+) are imported into the early secretory pathway by Golgi-resident transporters, but their handling and functions are not fully understood. Here, we show that Zn2+binds with high affinity to the pH-sensitive chaperone ERp44, modulating its localization and ability to retrieve clients like Ero1α and ERAP1 to the endoplasmic reticulum (ER). Silencing the Zn2+transporters that uptake Zn2+into the Golgi led to ERp44 dysfunction and increased secretion of Ero1α and ERAP1. High-resolution crystal structures of Zn2+-bound ERp44 reveal that Zn2+binds to a conserved histidine-cluster. The consequent large displacements of the regulatory C-terminal tail expose the substrate-binding surface and RDEL motif, ensuring client capture and retrieval. ERp44 also forms Zn2+-bridged homodimers, which dissociate upon client binding. Histidine mutations in the Zn2+-binding sites compromise ERp44 activity and localization. Our findings reveal a role of Zn2+as a key regulator of protein quality control at the ER-Golgi interface.