Zinc regulates ERp44-dependent protein quality control in the early secretory pathway

• Published in: Nature communications Vol. 10; no. 1; p. 603
• Main Authors: Watanabe, Satoshi, Amagai, Yuta, Sannino, Sara, Tempio, Tiziana, Anelli, Tiziana, Harayama, Manami, Masui, Shoji, Sorrentino, Ilaria, Yamada, Momo, Sitia, Roberto, Inaba, Kenji
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.02.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/89; 14/19; 631/45/612; 631/535/1266; 631/80/470; 82/16; 82/29; 82/80; 82/83; Aminopeptidases - metabolism; Binding sites; Binding Sites - genetics; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Crystal structure; Crystallography, X-Ray; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Golgi apparatus; Golgi Apparatus - metabolism; HeLa Cells; Hep G2 Cells; Histidine; Humanities and Social Sciences; Humans; Localization; Membrane Glycoproteins - metabolism; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Minor Histocompatibility Antigens - metabolism; Molecular Chaperones - chemistry; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; multidisciplinary; Mutation; Oxidoreductases - metabolism; pH effects; Protein Binding; Protein Conformation; Protein Multimerization; Proteins; Quality Control; RNA Interference; Science; Science (multidisciplinary); Secretion; Secretory Pathway; Substrates; Zinc; Zinc - chemistry; Zinc - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08429-1

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. Zinc ions (Zn 2+ ) are imported by Golgi-resident transporters but the function of zinc in the early secretory pathway has remained unknown. Here the authors find that Zn 2+ regulates protein quality control in the early secretory pathway by demonstrating that the pH-sensitive chaperone ERp44 binds Zn 2+ and solving the Zn 2+ -bound ERp44 structure.