{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T22:57:55Z","timestamp":1785365875878,"version":"3.55.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,12,15]],"date-time":"2017-12-15T00:00:00Z","timestamp":1513296000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,12,15]],"date-time":"2017-12-15T00:00:00Z","timestamp":1513296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Vitamin K epoxide reductase (VKOR) is an essential enzyme for vitamin K-dependent carboxylation, while the physiological function of its paralogous enzyme VKOR-like (VKORL) is yet unknown. Although these two enzymes share approximately 50% protein sequence homology, the membrane topology of VKOR is still in debate. Here, we explored the differences in the membrane topology and disulfide-linked oligomerization of these two enzymes. Results from mutating the critical amino acid residues in the disputed transmembrane (TM) regions revealed that the second TM domain in the proposed 4-TM model of VKOR does not function as an authentic TM helix; supporting VKOR is a 3-TM protein, which is different from VKORL. Additionally, altering the loop sequence between the two conserved cysteine residues of VKORL affects its activity, supporting the notion that the conserved loop cysteines of VKORL are involved in its active site regeneration. However, a similar mutation in VKOR does not affect its enzymatic activity. Finally, our results show that although both VKOR and VKORL form disulfide-linked oligomers, the cysteine residues involved in the oligomerization appear to be different. Overall, the structural and functional differences between VKOR and VKORL shown here indicate that VKORL might have a different physiological function other than recycling vitamin K.<\/jats:p>","DOI":"10.1038\/s41598-017-18008-3","type":"journal-article","created":{"date-parts":[[2017,12,11]],"date-time":"2017-12-11T10:57:02Z","timestamp":1512989822000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Vitamin K epoxide reductase and its paralogous enzyme have different structures and functions"],"prefix":"10.1038","volume":"7","author":[{"given":"Balaji Chandra Sekhar","family":"Sinhadri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da-Yun","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrel W.","family":"Stafford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Ke","family":"Tie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,12,15]]},"reference":[{"key":"18008_CR1","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1111\/j.1538-7836.2005.01419.x","volume":"3","author":"DW Stafford","year":"2005","unstructured":"Stafford, D. W. The vitamin K cycle. J Thromb Haemost \n                           3, 1873\u20131878, https:\/\/doi.org\/10.1111\/j.1538-7836.2005.01419.x (2005).","journal-title":"J Thromb Haemost"},{"key":"18008_CR2","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1194\/jlr.R045559","volume":"55","author":"MJ Shearer","year":"2014","unstructured":"Shearer, M. J. & Newman, P. Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis. J Lipid Res \n                           55, 345\u2013362, https:\/\/doi.org\/10.1194\/jlr.R045559 (2014).","journal-title":"J Lipid Res"},{"key":"18008_CR3","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1111\/jth.13217","volume":"14","author":"JK Tie","year":"2016","unstructured":"Tie, J. K. & Stafford, D. W. Structural and functional insights into enzymes of the vitamin K cycle. J Thromb Haemost \n                           14, 236\u2013247, https:\/\/doi.org\/10.1111\/jth.13217 (2016).","journal-title":"J Thromb Haemost"},{"key":"18008_CR4","doi-asserted-by":"publisher","first-page":"357","DOI":"10.3109\/10409238.2013.791659","volume":"48","author":"WD Van Horn","year":"2013","unstructured":"Van Horn, W. D. Structural and functional insights into human vitamin K epoxide reductase and vitamin K epoxide reductase-like1. Crit Rev Biochem Mol Biol \n                           48, 357\u2013372, https:\/\/doi.org\/10.3109\/10409238.2013.791659 (2013).","journal-title":"Crit Rev Biochem Mol Biol"},{"key":"18008_CR5","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1007\/s11239-016-1446-0","volume":"43","author":"A Zirlik","year":"2017","unstructured":"Zirlik, A. & Bode, C. Vitamin K antagonists: relative strengths and weaknesses vs. direct oral anticoagulants for stroke prevention in patients with atrial fibrillation. J Thromb Thrombolysis \n                           43, 365\u2013379, https:\/\/doi.org\/10.1007\/s11239-016-1446-0 (2017).","journal-title":"J Thromb Thrombolysis"},{"key":"18008_CR6","doi-asserted-by":"publisher","first-page":"135","DOI":"10.3945\/an.111.001719","volume":"3","author":"MA Rishavy","year":"2012","unstructured":"Rishavy, M. A. & Berkner, K. L. Vitamin K oxygenation, glutamate carboxylation, and processivity: defining the three critical facets of catalysis by the vitamin K-dependent carboxylase. Adv Nutr \n                           3, 135\u2013148, https:\/\/doi.org\/10.3945\/an.111.001719 (2012).","journal-title":"Adv Nutr"},{"key":"18008_CR7","doi-asserted-by":"publisher","first-page":"166","DOI":"10.3945\/an.111.001628","volume":"3","author":"E Theuwissen","year":"2012","unstructured":"Theuwissen, E., Smit, E. & Vermeer, C. The role of vitamin K in soft-tissue calcification. Adv Nutr \n                           3, 166\u2013173, https:\/\/doi.org\/10.3945\/an.111.001628 (2012).","journal-title":"Adv Nutr"},{"key":"18008_CR8","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1160\/TH07-04-0266","volume":"98","author":"EC Cranenburg","year":"2007","unstructured":"Cranenburg, E. C., Schurgers, L. J. & Vermeer, C. Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost \n                           98, 120\u2013125 (2007).","journal-title":"Thromb Haemost"},{"key":"18008_CR9","doi-asserted-by":"publisher","first-page":"10540","DOI":"10.1074\/jbc.M413982200","volume":"280","author":"N Wajih","year":"2005","unstructured":"Wajih, N., Sane, D. C., Hutson, S. M. & Wallin, R. Engineering of a recombinant vitamin K-dependent gamma-carboxylation system with enhanced gamma-carboxyglutamic acid forming capacity: evidence for a functional CXXC redox center in the system. J Biol Chem \n                           280, 10540\u201310547, https:\/\/doi.org\/10.1074\/jbc.M413982200 (2005).","journal-title":"J Biol Chem"},{"key":"18008_CR10","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.tibs.2004.04.004","volume":"29","author":"L Goodstadt","year":"2004","unstructured":"Goodstadt, L. & Ponting, C. P. Vitamin K epoxide reductase: homology, active site and catalytic mechanism. Trends Biochem Sci \n                           29, 289\u2013292, https:\/\/doi.org\/10.1016\/j.tibs.2004.04.004 (2004).","journal-title":"Trends Biochem Sci"},{"key":"18008_CR11","doi-asserted-by":"publisher","first-page":"7279","DOI":"10.1021\/bi700527j","volume":"46","author":"DY Jin","year":"2007","unstructured":"Jin, D. Y., Tie, J. K. & Stafford, D. W. The conversion of vitamin K epoxide to vitamin K quinone and vitamin K quinone to vitamin K hydroquinone uses the same active site cysteines. Biochemistry \n                           46, 7279\u20137283, https:\/\/doi.org\/10.1021\/bi700527j (2007).","journal-title":"Biochemistry"},{"key":"18008_CR12","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1160\/TH05-02-0082","volume":"94","author":"S Rost","year":"2005","unstructured":"Rost, S. et al. Site-directed mutagenesis of coumarin-type anticoagulant-sensitive VKORC1: evidence that highly conserved amino acids define structural requirements for enzymatic activity and inhibition by warfarin. Thromb Haemost \n                           94, 780\u2013786, https:\/\/doi.org\/10.1160\/TH05-02-0082 (2005).","journal-title":"Thromb Haemost"},{"key":"18008_CR13","doi-asserted-by":"publisher","first-page":"2262","DOI":"10.1111\/j.1742-4658.2012.08593.x","volume":"279","author":"Y Sato","year":"2012","unstructured":"Sato, Y. & Inaba, K. Disulfide bond formation network in the three biological kingdoms, bacteria, fungi and mammals. FEBS J \n                           279, 2262\u20132271, https:\/\/doi.org\/10.1111\/j.1742-4658.2012.08593.x (2012).","journal-title":"FEBS J"},{"key":"18008_CR14","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1038\/emboj.2009.21","volume":"28","author":"K Inaba","year":"2009","unstructured":"Inaba, K. et al. Dynamic nature of disulphide bond formation catalysts revealed by crystal structures of DsbB. EMBO J \n                           28, 779\u2013791, https:\/\/doi.org\/10.1038\/emboj.2009.21 (2009).","journal-title":"EMBO J"},{"key":"18008_CR15","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1016\/j.cell.2006.10.034","volume":"127","author":"K Inaba","year":"2006","unstructured":"Inaba, K. et al. Crystal structure of the DsbB-DsbA complex reveals a mechanism of disulfide bond generation. Cell \n                           127, 789\u2013801, https:\/\/doi.org\/10.1016\/j.cell.2006.10.034 (2006).","journal-title":"Cell"},{"key":"18008_CR16","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1016\/S0092-8674(00)00180-X","volume":"103","author":"F Katzen","year":"2000","unstructured":"Katzen, F. & Beckwith, J. Transmembrane electron transfer by the membrane protein DsbD occurs via a disulfide bond cascade. Cell \n                           103, 769\u2013779 (2000).","journal-title":"Cell"},{"key":"18008_CR17","doi-asserted-by":"publisher","first-page":"7267","DOI":"10.1074\/jbc.M110.172213","volume":"286","author":"MA Rishavy","year":"2011","unstructured":"Rishavy, M. A., Usubalieva, A., Hallgren, K. W. & Berkner, K. L. Novel insight into the mechanism of the vitamin K oxidoreductase (VKOR): electron relay through Cys43 and Cys51 reduces VKOR to allow vitamin K reduction and facilitation of vitamin K-dependent protein carboxylation. J Biol Chem \n                           286, 7267\u20137278, https:\/\/doi.org\/10.1074\/jbc.M110.172213 (2011).","journal-title":"J Biol Chem"},{"key":"18008_CR18","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/nature08720","volume":"463","author":"W Li","year":"2010","unstructured":"Li, W. et al. Structure of a bacterial homologue of vitamin K epoxide reductase. Nature \n                           463, 507\u2013512, https:\/\/doi.org\/10.1038\/nature08720 (2010).","journal-title":"Nature"},{"key":"18008_CR19","doi-asserted-by":"publisher","first-page":"1556","DOI":"10.1111\/jth.12306","volume":"11","author":"JK Tie","year":"2013","unstructured":"Tie, J. K., Jin, D. Y., Tie, K. & Stafford, D. W. Evaluation of warfarin resistance using transcription activator-like effector nucleases-mediated vitamin K epoxide reductase knockout HEK293 cells. J Thromb Haemost \n                           11, 1556\u20131564, https:\/\/doi.org\/10.1111\/jth.12306 (2013).","journal-title":"J Thromb Haemost"},{"key":"18008_CR20","doi-asserted-by":"publisher","first-page":"33945","DOI":"10.1074\/jbc.M112.402941","volume":"287","author":"JK Tie","year":"2012","unstructured":"Tie, J. K., Jin, D. Y. & Stafford, D. W. Human vitamin K epoxide reductase and its bacterial homologue have different membrane topologies and reaction mechanisms. J Biol Chem \n                           287, 33945\u201333955, https:\/\/doi.org\/10.1074\/jbc.M112.402941 (2012).","journal-title":"J Biol Chem"},{"key":"18008_CR21","doi-asserted-by":"publisher","first-page":"16410","DOI":"10.1074\/jbc.M500765200","volume":"280","author":"JK Tie","year":"2005","unstructured":"Tie, J. K., Nicchitta, C., von Heijne, G. & Stafford, D. W. Membrane topology mapping of vitamin K epoxide reductase by in vitro translation\/cotranslocation. J Biol Chem \n                           280, 16410\u201316416, https:\/\/doi.org\/10.1074\/jbc.M500765200 (2005).","journal-title":"J Biol Chem"},{"key":"18008_CR22","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1038\/341456a0","volume":"341","author":"G von Heijne","year":"1989","unstructured":"von Heijne, G. Control of topology and mode of assembly of a polytopic membrane protein by positively charged residues. Nature \n                           341, 456\u2013458, https:\/\/doi.org\/10.1038\/341456a0 (1989).","journal-title":"Nature"},{"key":"18008_CR23","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1016\/j.bbamcr.2013.12.007","volume":"1843","author":"M Bogdanov","year":"2014","unstructured":"Bogdanov, M., Dowhan, W. & Vitrac, H. Lipids and topological rules governing membrane protein assembly. 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J Thromb Haemost \n                           12, 112\u2013114, https:\/\/doi.org\/10.1111\/jth.12450 (2014).","journal-title":"J Thromb Haemost"},{"key":"18008_CR26","doi-asserted-by":"publisher","first-page":"9396","DOI":"10.1074\/jbc.M113.534446","volume":"289","author":"JK Tie","year":"2014","unstructured":"Tie, J. K., Jin, D. Y. & Stafford, D. W. Conserved loop cysteines of vitamin K epoxide reductase complex subunit 1-like 1 (VKORC1L1) are involved in its active site regeneration. J Biol Chem \n                           289, 9396\u20139407, https:\/\/doi.org\/10.1074\/jbc.M113.534446 (2014).","journal-title":"J Biol Chem"},{"key":"18008_CR27","doi-asserted-by":"publisher","first-page":"28733","DOI":"10.1074\/jbc.M113.457119","volume":"288","author":"A Hammed","year":"2013","unstructured":"Hammed, A. et al. VKORC1L1, an enzyme rescuing the vitamin K 2,3-epoxide reductase activity in some extrahepatic tissues during anticoagulation therapy. J Biol Chem \n                           288, 28733\u201328742, https:\/\/doi.org\/10.1074\/jbc.M113.457119 (2013).","journal-title":"J Biol Chem"},{"key":"18008_CR28","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1038\/nature02214","volume":"427","author":"S Rost","year":"2004","unstructured":"Rost, S. et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature \n                           427, 537\u2013541, https:\/\/doi.org\/10.1038\/nature02214 (2004).","journal-title":"Nature"},{"key":"18008_CR29","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1160\/TH09-03-0204","volume":"101","author":"G Spohn","year":"2009","unstructured":"Spohn, G. et al. VKORC1 deficiency in mice causes early postnatal lethality due to severe bleeding. Thromb Haemost \n                           101, 1044\u20131050 (2009).","journal-title":"Thromb Haemost"},{"key":"18008_CR30","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1016\/j.sbi.2004.07.007","volume":"14","author":"A Senes","year":"2004","unstructured":"Senes, A., Engel, D. E. & DeGrado, W. F. Folding of helical membrane proteins: the role of polar, GxxxG-like and proline motifs. Curr Opin Struct Biol \n                           14, 465\u2013479, https:\/\/doi.org\/10.1016\/j.sbi.2004.07.007 (2004).","journal-title":"Curr Opin Struct Biol"},{"key":"18008_CR31","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/j.jmb.2003.10.062","volume":"335","author":"M Orzaez","year":"2004","unstructured":"Orzaez, M., Salgado, J., Gimenez-Giner, A., Perez-Paya, E. & Mingarro, I. Influence of proline residues in transmembrane helix packing. 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J Cell Biol \n                           208, 761\u2013776, https:\/\/doi.org\/10.1083\/jcb.201409111 (2015).","journal-title":"J Cell Biol"},{"key":"18008_CR34","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1182\/blood-2013-12-545988","volume":"124","author":"KJ Czogalla","year":"2014","unstructured":"Czogalla, K. J., Biswas, A., Rost, S., Watzka, M. & Oldenburg, J. The Arg98Trp mutation in human VKORC1 causing VKCFD2 disrupts a di-arginine-based ER retention motif. Blood \n                           124, 1354\u20131362, https:\/\/doi.org\/10.1182\/blood-2013-12-545988 (2014).","journal-title":"Blood"},{"key":"18008_CR35","doi-asserted-by":"publisher","first-page":"31556","DOI":"10.1074\/jbc.M113.497297","volume":"288","author":"MA Rishavy","year":"2013","unstructured":"Rishavy, M. A. et al. The vitamin K oxidoreductase is a multimer that efficiently reduces vitamin K epoxide to hydroquinone to allow vitamin K-dependent protein carboxylation. J Biol Chem \n                           288, 31556\u201331566, https:\/\/doi.org\/10.1074\/jbc.M113.497297 (2013).","journal-title":"J Biol Chem"},{"key":"18008_CR36","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1160\/TH10-07-0483","volume":"105","author":"A Schaafhausen","year":"2011","unstructured":"Schaafhausen, A., Rost, S., Oldenburg, J. & Muller, C. R. Identification of VKORC1 interaction partners by split-ubiquitin system and coimmunoprecipitation. Thromb Haemost \n                           105, 285\u2013294, https:\/\/doi.org\/10.1160\/TH10-07-0483 (2011).","journal-title":"Thromb Haemost"},{"key":"18008_CR37","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/nsmb.3333","volume":"24","author":"G Shen","year":"2017","unstructured":"Shen, G. et al. Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer. Nat Struct Mol Biol \n                           24, 69\u201376, https:\/\/doi.org\/10.1038\/nsmb.3333 (2017).","journal-title":"Nat Struct Mol Biol"},{"key":"18008_CR38","doi-asserted-by":"publisher","first-page":"15085","DOI":"10.1074\/jbc.M110.210971","volume":"286","author":"P Westhofen","year":"2011","unstructured":"Westhofen, P. et al. Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1 (VKORC1L1) mediates vitamin K-dependent intracellular antioxidant function. J Biol Chem \n                           286, 15085\u201315094, https:\/\/doi.org\/10.1074\/jbc.M110.210971 (2011).","journal-title":"J Biol Chem"},{"key":"18008_CR39","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/bs.mie.2016.10.015","volume":"584","author":"JK Tie","year":"2017","unstructured":"Tie, J. K. & Stafford, D. W. Functional Study of the Vitamin K Cycle Enzymes in Live Cells. Methods Enzymol \n                           584, 349\u2013394, https:\/\/doi.org\/10.1016\/bs.mie.2016.10.015 (2017).","journal-title":"Methods Enzymol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-18008-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-18008-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-18008-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T16:27:24Z","timestamp":1671812844000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-18008-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12,15]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["18008"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-18008-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12,15]]},"assertion":[{"value":"28 July 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 December 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 December 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"17632"}}