Highly Dynamic Polynuclear Metal Cluster Revealed in a Single Metallothionein Molecule
Guodong Yuan1, Felipe Curtolo2, Yibing Deng1
1State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210023, China.
Research (Washington, D.C.)
|August 9, 2021
Summary
Human metallothionein (MT) protein dynamics revealed. Single-molecule and simulation methods show MT
Area of Science:
- Biochemistry
- Structural Biology
- Biophysics
Background:
- Human metallothionein (MT) is a crucial protein for metal homeostasis and detoxification.
- MT features two domains with polynuclear metal clusters and a hexatomic ring structure.
- The intrinsically disordered apoprotein and dynamic metal-thiolate bonds complicate structural analysis.
Purpose of the Study:
- To investigate the metal cluster rupture mechanism and chemical stability in a single metallothionein molecule.
- To understand the dynamic structural behavior of the Zn4S11 cluster in the α domain during unfolding.
Main Methods:
- Combined single-molecule approaches with multiscale molecular simulations.
- Focused on the Zn4S11 cluster in the α domain of human metallothionein.
- Analyzed unfolding pathways and metal-thiolate bond dynamics.
Main Results:
- Observed unusual multiple unfolding pathways and intermediates with varying metal-thiolate bond rupture.
- Identified that unfolding proceeds through a distribution of protein conformational substates.
- Simulations revealed metal cluster rearrangement, with metal-thiolate bonds forming and breaking independently of backbone changes.
Conclusions:
- Human metallothionein exhibits a highly dynamic polynuclear metal cluster with multiple conformational states.
- This dynamic nature contributes to MT's metal-binding promiscuity and diverse cellular functions.
- The findings challenge traditional ensemble measurements by highlighting single-molecule dynamics.
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