Zn2+-dependent functional switching of ERp18, an ER-resident thioredoxin-like protein.

Chika Tsutsumi, Kaiku Uegaki, Riyuji Yamashita, Ryo Ushioda, Kazuhiro Nagata

Cell reports 2024 Feb 27

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ERp18 is an endoplasmic reticulum (ER)-resident thioredoxin (Trx) family protein, similar to cytosolic Trx1. The Trx-like domain occupies a major portion of the whole ERp18 structure, which is postulated to be an ER paralog of cytosolic Trx1. Here, we elucidate that zinc ion (Zn2+) binds ERp18 through its catalytic motif, triggering oligomerization of ERp18 from a monomer to a trimer. While the monomeric ERp18 has disulfide oxidoreductase activity, the trimeric ERp18 acquires scavenger activity for hydrogen peroxide (H2O2) in the ER. Depletion of ERp18 thus causes the accumulation of H2O2, which is produced during the oxidative folding of nascent polypeptides in the ER. ERp18 knockdown in C. elegans without Prx4 and GPx7/8, both of which are also known to have H2O2 scavenging activity in the ER, shortened the lifespan, suggesting that ERp18 may form a primitive and essential H2O2 scavenging system for the maintenance of redox homeostasis in the ER. Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Chika Tsutsumi, Kaiku Uegaki, Riyuji Yamashita, Ryo Ushioda, Kazuhiro Nagata. Zn2+-dependent functional switching of ERp18, an ER-resident thioredoxin-like protein. Cell reports. 2024 Feb 27;43(2):113682