TY - JOUR
T1 - Intramembrane Thiol Oxidoreductases
T2 - Evolutionary Convergence and Structural Controversy
AU - Li, Shuang
AU - Shen, Guomin
AU - Li, Weikai
N1 - Funding Information:
*Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Telephone: +1 314-362-8687. E-mail: weikai@wustl.edu. ORCID Weikai Li: 0000-0002-8711-1904 Funding G.S. is supported by the National Natural Science Foundation of China (81770140). W.L. is supported by the National Heart, Lung and Blood Institute (R01 HL121718). Notes The authors declare no competing financial interest.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2018/1/23
Y1 - 2018/1/23
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85041073828&partnerID=8YFLogxK
U2 - 10.1021/acs.biochem.7b00876
DO - 10.1021/acs.biochem.7b00876
M3 - Review article
C2 - 29064673
AN - SCOPUS:85041073828
VL - 57
SP - 258
EP - 266
JO - Biochemistry
JF - Biochemistry
SN - 0006-2960
IS - 3
ER -