Intramembrane Thiol Oxidoreductases: Evolutionary Convergence and Structural Controversy

Biochemistry. 2018 Jan 23;57(3):258-266. doi: 10.1021/acs.biochem.7b00876. Epub 2017 Nov 7.

Abstract

During oxidative protein folding, disulfide bond formation is catalyzed by thiol oxidoreductases. Through dedicated relay pathways, the disulfide is generated in donor enzymes, passed to carrier enzymes, and subsequently delivered to target proteins. The eukaryotic disulfide donors are flavoenzymes, Ero1 in the endoplasmic reticulum and Erv1 in mitochondria. In prokaryotes, disulfide generation is coupled to quinone reduction, catalyzed by intramembrane donor enzymes, DsbB and VKOR. To catalyze de novo disulfide formation, these different disulfide donors show striking structural convergence at several levels. They share a four-helix bundle core structure at their active site, which contains a CXXC motif at a helical end. They have also evolved a flexible loop with shuttle cysteines to transfer electrons to the active site and relay the disulfide bond to the carrier enzymes. Studies of the prokaryotic VKOR, however, have stirred debate about whether the human homologue adopts the same topology with four transmembrane helices and uses the same electron-transfer mechanism. The controversies have recently been resolved by investigating the human VKOR structure and catalytic process in living cells with a mass spectrometry-based approach. Structural convergence between human VKOR and the disulfide donors is found to underlie cofactor reduction, disulfide generation, and electron transfer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalysis
  • Conserved Sequence
  • Disulfides / chemistry
  • Evolution, Molecular*
  • Humans
  • Isomerism
  • Oxidoreductases Acting on Sulfur Group Donors / chemistry*
  • Protein Folding
  • Protein Structure, Secondary
  • Sulfhydryl Compounds / chemistry*
  • Vitamin K Epoxide Reductases / chemistry*

Substances

  • Disulfides
  • Sulfhydryl Compounds
  • Vitamin K Epoxide Reductases
  • Oxidoreductases Acting on Sulfur Group Donors