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Zinc regulates ERp44-dependent protein quality control in the early secretory pathway
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Journal Article
Zinc regulates ERp44-dependent protein quality control in the early secretory pathway
2019
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/19
/ 82/16
/ 82/29
/ 82/80
/ 82/83
/ Aminopeptidases - metabolism
/ Cation Transport Proteins - genetics
/ Cation Transport Proteins - metabolism
/ Endoplasmic Reticulum - metabolism
/ Golgi Apparatus - metabolism
/ Humanities and Social Sciences
/ Humans
/ Ions
/ 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
/ Mutation
/ Oxidoreductases - metabolism
/ Proteins
/ Science
/ Zinc
