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Abstract Zinc ions (Zn 2+ ) are imported into the early secretory pathway by Golgi-resident transporters, but their handling and functions are not fully understood. Here, we show that Zn 2+ 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 Zn 2+ transporters that uptake Zn 2+ into the Golgi led to ERp44 dysfunction and increased secretion of Ero1α and ERAP1. High-resolution crystal structures of Zn 2+ -bound ERp44 reveal that Zn 2+ 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 Zn 2+ -bridged homodimers, which dissociate upon client binding. Histidine mutations in the Zn 2+ -binding sites compromise ERp44 activity and localization. Our findings reveal a role of Zn 2+ as a key regulator of protein quality control at the ER-Golgi interface.
Watanabe et al. (Tue,) studied this question.