Metallothionein Zn2+- and Cu2+-clusters from first-principles calculations
Per Greisen1, Jakob B Jespersen, Kasper P Kepp
1Technical University of Denmark, DTU Physics, 2800, Kongens Lyngby, Denmark.
Dalton Transactions (Cambridge, England : 2003)
|December 21, 2011
Summary
Oxidative stress disrupts zinc (Zn) binding in metallothioneins (MT) by introducing copper (Cu) intermediates. This leads to the loss of Zn and the formation of dysfunctional Cu-bound MT, impacting cellular metal homeostasis.
Area of Science:
- Biochemistry
- Computational Chemistry
- Toxicology
Background:
- Metallothioneins (MTs) are crucial proteins for cellular metal detoxification and homeostasis.
- Oxidative stress can alter the metal-binding properties of MTs, particularly involving zinc (Zn) and copper (Cu).
Purpose of the Study:
- To investigate the impact of oxidative stress-induced Cu(II) intermediates on Zn-binding to MT.
- To elucidate the mechanism by which Cu(II) binding leads to the formation of dysfunctional Cu(I)MT clusters.
Main Methods:
- Density Functional Theory (DFT) calculations were employed to model Zn(II) and Cu(II) clusters within MT.
- Analysis of metal-thiolate bond lengths and electron densities provided insights into electronic structure changes.
- Protein backbone constraints were used to assess the sensitivity of cluster electronic structure to conformational changes.
Main Results:
- DFT calculations accurately predicted metal-thiolate bond lengths (±0.02-0.03 Å).
- Cu(II) binding was found to weaken Zn-S bonds, impairing Zn(II) transfer.
- Smaller β-clusters within MT were identified as more susceptible to modification.
Conclusions:
- Oxidative stress-mediated Cu(II) binding disrupts Zn homeostasis by promoting Zn(II) release from MT.
- This process facilitates the formation of dysfunctional Cu(I)MT, highlighting a novel mechanism of MT dysfunction under oxidative stress.
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