The membrane topology of vitamin K epoxide reductase is conserved between human isoforms and the bacterial enzyme

The Biochemical Journal
Zhenbo CaoNeil Bulleid

Abstract

The membrane topology of vitamin K epoxide reductase (VKOR) is controversial with data supporting both a three transmembrane and a four transmembrane model. The positioning of the transmembrane domains and the loops between these domains is critical if we are to understand the mechanism of vitamin K oxidation and its recycling by members of the thioredoxin family of proteins and the mechanism of action of warfarin, an inhibitor of VKOR. Here we show that both mammalian VKOR isoforms adopt the same topology, with the large loop between transmembrane one and two facing the lumen of the endoplasmic reticulum (ER). We used a redox sensitive green fluorescent protein (GFP) fused to the N- or C-terminus to show that these regions face the cytosol, and introduction of glycosylation sites along with mixed disulfide formation with thioredoxin-like transmembrane protein (TMX) to demonstrate ER localization of the major loop. The topology is identical with the bacterial homologue from Synechococcussp., for which the structure and mechanism of recycling has been characterized. Our results provide a resolution to the membrane topology controversy and support previous results suggesting a role for members of the ER protein disulfide isomeras...Continue Reading

References

Aug 25, 1989·Nucleic Acids Research·A HemsleyD J Galas
Aug 1, 1995·Proceedings of the National Academy of Sciences of the United States of America·O BoussifJ P Behr
Jul 11, 2003·The EMBO Journal·Veit Goder, Martin Spiess
Jul 28, 2004·Trends in Biochemical Sciences·Leo Goodstadt, Chris P Ponting
Feb 18, 2005·The Journal of Biological Chemistry·Jian-Ke TieDarrel W Stafford
Oct 23, 2008·The Plant Journal : for Cell and Molecular Biology·Thorsten BrachAndreas J Meyer
Sep 17, 2009·The Journal of Biological Chemistry·Marcus GutscherTobias P Dick
Jan 30, 2010·Nature·Weikai LiTom A Rapoport
Aug 11, 2010·Proceedings of the National Academy of Sciences of the United States of America·Sol SchulmanTom A Rapoport
Nov 26, 2010·Thrombosis and Haemostasis·Anne SchaafhausenClemens R Müller
Nov 3, 2011·The EMBO Journal·Emily M LynesThomas Simmen
May 15, 2012·Science·Melissa VosPatrik Verstreken
Apr 17, 2013·The Journal of Cell Biology·Edward AvezovDavid Ron
May 2, 2013·Critical Reviews in Biochemistry and Molecular Biology·Wade D Van Horn
Aug 8, 2015·Molecular Biology of the Cell·Giorgia Brambilla PisoniMaurizio Molinari
Aug 20, 2015·Nutrients·Katrin J CzogallaJohannes Oldenburg

❮ Previous
Next ❯

Citations

Dec 6, 2016·Nature Structural & Molecular Biology·Guomin ShenWeikai Li
Jul 13, 2017·Chemical Reviews·Deborah Fass, Colin Thorpe

❮ Previous
Next ❯

Related Concepts

Related Feeds

Bacterial Protein Structures

Bacterial protein structures can expedite the development of novel antibiotics. Here is the latest research on bacterial proteins and the resolution of their structures.

Bacterial Protein Structures (ASM)

Bacterial protein structures can expedite the development of novel antibiotics. Here is the latest research on bacterial proteins and the resolution of their structures.

Related Papers

Proceedings of the National Academy of Sciences of the United States of America
Sol SchulmanTom A Rapoport
Acta Chemica Scandinavica. Series B: Organic Chemistry and Biochemistry
J SeidegårdF Oesch
Journal of Thrombosis and Haemostasis : JTH
S WuL G Pedersen
© 2022 Meta ULC. All rights reserved