Growth inhibitory factor/metallothionein-3 is a sulfane sulfur-binding protein
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. In this study, we identified growth inhibitory factor (GIF)/metallothionein-3 (MT-3) as a sulfane sulfur-binding protein from mouse brain. We also report here that cysteine-bound sulfane sulfur atoms serve as ligands to hold and release zinc ions in GIF/MT-3 with an unexpected C–S–S–Zn structure. Oxidation of such a zinc/persulfide cluster in Zn 7 GIF/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 Zn 7 GIF/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.
Authors
- Tomoaki Ida (ORCID: https://orcid.org/0000-0002-4443-6127)
- Toru Matsui (ORCID: https://orcid.org/0000-0001-9847-5925)
- George Devitt (ORCID: https://orcid.org/0000-0001-7179-4459)
- Yasuhiro Shinkai (ORCID: https://orcid.org/0000-0003-1772-5342)
- Jon M. Fukuto (ORCID: https://orcid.org/0000-0002-0014-160X)
- Yoshito Kumagai (ORCID: https://orcid.org/0000-0003-4523-8234)
- Tang‐Long Shen (ORCID: https://orcid.org/0000-0001-6264-3608)
- Yunjie Ding
- Sumeet Mahajan (ORCID: https://orcid.org/0000-0001-8923-6666)
- Motohiro Nishida (ORCID: https://orcid.org/0000-0002-2587-5458)
- Yasuteru Shigeta (ORCID: https://orcid.org/0000-0002-3219-6007)
- Masahiro Akiyama (ORCID: https://orcid.org/0000-0003-2921-4160)
- Takaaki Akaike (ORCID: https://orcid.org/0000-0002-0623-1710)
Institutions
- Kyushu University (JP)
- Johns Hopkins University (US)
- University of Tsukuba (JP)
- Tokyo University of Pharmacy and Life Sciences (JP)
- National Taiwan University (TW)
- National Institutes of Natural Sciences (JP)
- Tohoku University (JP)
- National Institute for Physiological Sciences (JP)
- Living Systems (United States) (US)
- University of Southampton (GB)
- The Exploratory Research Center on Life and Living Systems (JP)
Publication Details
- Journal
- eLife
- Published
- 2025-11-14
- DOI
- https://doi.org/10.7554/elife.92120.4
- Citations
- 3
- Primary Topic
- Trace Elements in Health
- Type
- article
- Field-Weighted Citation Impact
- 3.36