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Intramembrane Thiol Oxidoreductases: Evolutionary Convergence and Structural Controversy.
Shuang Li1, Guomin Shen1,2, Weikai Li1
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine , St. Louis, Missouri 63110, United States.
Biochemistry
|October 25, 2017
Summary
Disulfide bond formation in cells relies on thiol oxidoreductases. New research confirms human Vitamin K epoxide reductase (VKOR) shares structural and catalytic mechanisms with other disulfide bond donors, resolving previous debates.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Disulfide bond formation is crucial for oxidative protein folding.
- Thiol oxidoreductases catalyze disulfide bond formation through relay pathways.
- Eukaryotic disulfide donors include Ero1 (ER) and Erv1 (mitochondria); prokaryotic donors are DsbB and VKOR.
Purpose of the Study:
- To investigate the structure and catalytic mechanism of human VKOR.
- To resolve controversies regarding human VKOR's topology and electron-transfer mechanism.
- To compare human VKOR with other disulfide donors.
Main Methods:
- In vivo studies using a mass spectrometry-based approach.
- Structural analysis of human VKOR.
- Investigation of the catalytic process in living cells.
Main Results:
- Human VKOR exhibits a four-helix bundle core structure with a CXXC motif, similar to other disulfide donors.
- A flexible loop with shuttle cysteines facilitates electron transfer.
- Structural convergence underlies cofactor reduction, disulfide generation, and electron transfer in human VKOR.
Conclusions:
- Human VKOR shares significant structural and mechanistic similarities with prokaryotic and eukaryotic disulfide donors.
- These findings resolve debates about human VKOR's function and evolutionary conservation.
- The study highlights convergent evolution in disulfide bond formation pathways.
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