Growth inhibitory factor/metallothionein-3 is a sulfane sulfur-binding protein

Yasuhiro Shinkai; Yunjie Ding; Toru Matsui; George Devitt; Masahiro Akiyama; Tang‐Long Shen; Motohiro Nishida; Tomoaki Ida; Takaaki Akaike; Sumeet Mahajan; Jon M. Fukuto; Yasuteru Shigeta; Yoshito Kumagai

doi:10.7554/elife.92120

BiochemistryeLifeNov 30, 2023

Peer-reviewed journal article

Growth inhibitory factor/metallothionein-3 is a sulfane sulfur-binding protein

Yasuhiro Shinkai iD, Yunjie Ding, Toru Matsui iD, George Devitt iD, Masahiro Akiyama iD, Tang‐Long Shen iD, Motohiro Nishida iD, Tomoaki Ida iD, Takaaki Akaike iD, Sumeet Mahajan iD, Jon M. Fukuto iD, Yasuteru Shigeta iD, Yoshito Kumagai iD

Abstract

Cysteine-bound sulfane sulfur atoms in proteins have received much attention as key factors in cellular redox homeostasis. However, the role of sulfane sulfur in zinc regulation has been underinvestigated. We report here that cysteine-bound sulfane sulfur atoms serve as ligands to hold and release zinc ions in growth inhibitory factor (GIF)/metallothionein-3 (MT-3) with an unexpected C-S-S-Zn structure. Oxidation of such a zinc/persulfide cluster in Zn7GIF/MT-3 results in the release of zinc ions, and intramolecular tetrasulfide bridges in apo-GIF/MT-3 efficiently undergo S-S bond cleavage by thioredoxin to regenerate Zn7GIF/MT-3. Three-dimensional molecular modeling confirmed the critical role of the persulfide group in the thermostability and Zn-binding affinity of GIF/MT-3. The present discovery raises the fascinating possibility that the function of other Zn-binding proteins is controlled by sulfane sulfur.

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