Human Vitamin K Epoxide Reductase as a Target of its Redox Protein

Human Vitamin K epoxide reductase (hVKORC1) is a key enzyme to reduce vitamin K. Such function requires activation of the enzyme by a redox partner delivering reducing equivalents through thioldisulphide exchange reactions. The activation process represents a first and less studied step in hVKORC1 vital cycle, involving the oxidised luminal loop (L-loop) and a reduced thioredoxin protein (Trx), which is yet undefined for hVKORC1. A careful in silico study, based on molecular dynamic (MD) simulations of hVKORC1 in oxidised state, and a comparative analysis of four Trx proteins-protein disulphide isomerase (PDI), endoplasmic reticulum oxidoreductase (ERp18), thioredoxin-related transmembrane protein 1 (Tmx1) and thioredoxin-related transmembrane protein 4 (Tmx4)), viewed as the most probable reducers of hVKORC1-in their sequence, secondary and tertiary structure, dynamics, intraprotein interactions and composition of the surface exposed to the target-provided the identification of putative recognition/binding sites on each isolated protein. PDI was suggested as the most probable hVKORC1 partner. By probing the alternative orientation of PDI with respect to hVKORC1, two PDI-VKOR models were proposed and one of them considered as precursor for thiol-disulphide exchange reactions.