Structural domain plasticity drives Zn(II) distribution and buffering in metallothionein-3
Manuel David Peris-Díaz1,2, Eduard H T M Ebberink1, Jan Fiala1
1Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584 CH, The Netherlands.
Chemical Communications (Cambridge, England)
|April 20, 2026
Summary
This study reveals how zinc ions are distributed in metallothionein-3, a protein crucial for zinc metabolism. The findings show a dynamic process involving protein domains that helps regulate zinc levels in cells.
Area of Science:
- Biochemistry
- Structural Biology
- Metabolomics
Background:
- Metallothioneins (MTs) are cysteine-rich proteins involved in zinc homeostasis.
- Metallothionein-3 (MT-3) plays a specific role in the central nervous system.
- Understanding Zn(II) distribution in MT-3 is key to elucidating its regulatory functions.
Purpose of the Study:
- To map the distribution of zinc ions (Zn(II)) in partially metalated MT-3 species.
- To investigate the mechanism of Zn(II) dissociation from MT-3.
- To understand the role of MT-3 in cellular zinc buffering.
Main Methods:
- Integrated mass spectrometry-based approaches.
- Molecular dynamics simulations.
- Analysis of partially metalated Zn4-6-metallothionein-3 species.
Main Results:
- Detailed mapping of Zn(II) distribution across MT-3 domains.
- Identified sequential Zn(II) dissociation involving both α- and β-domains.
- Characterized a structurally plastic, interdomain mechanism.
Conclusions:
- MT-3 utilizes a dynamic interdomain mechanism for Zn(II) release.
- This mechanism facilitates regulatory zinc buffering at physiological zinc concentrations (pZn).
- Findings provide insights into MT-3's role in zinc metabolism and neuronal function.
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