Wu, S. M., Cheung, W. F., Frazier, D. & Stafford, D. W. Cloning and expression of the cDNA for human γ-glutamyl carboxylase. Science 254, 1634–1636 (1991).
Google Scholar
Furie, B., Bouchard, B. A. & Furie, B. C. Vitamin K-dependent biosynthesis of γ-carboxyglutamic acid. Blood 93, 1798–1808 (1999).
Google Scholar
Berkner, K. L. Vitamin K-dependent carboxylation. Vitam. Horm. 78, 131–156 (2008).
Google Scholar
Mladenka, P. et al. Vitamin K—sources, physiological role, kinetics, deficiency, detection, therapeutic use, and toxicity. Nutr. Rev. 80, 677–698 (2022).
Google Scholar
Stafford, D. W. The vitamin K cycle. J. Thromb. Haemost. 3, 1873–1878 (2005).
Google Scholar
Shearer, M. J. & Okano, T. Key pathways and regulators of vitamin K function and intermediary metabolism. Annu. Rev. Nutr. 38, 127–151 (2018).
Google Scholar
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. 3, 135–148 (2012).
Google Scholar
Li, T. et al. Identification of the gene for vitamin K epoxide reductase. Nature 427, 541–544 (2004).
Google Scholar
Rost, S. et al. Mutations in cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427, 537–541 (2004).
Google Scholar
Furie, B. & Furie, B. C. The molecular basis of blood coagulation. Cell 53, 505–518 (1988).
Google Scholar
Poser, J. W., Esch, F. S., Ling, N. C. & Price, P. A. Isolation and sequence of the vitamin K-dependent protein from human bone. Undercarboxylation of the first glutamic acid residue. J. Biol. Chem. 255, 8685–8691 (1980).
Google Scholar
Karsenty, G. & Olson, E. N. Bone and muscle endocrine functions: unexpected paradigms of inter-organ communication. Cell 164, 1248–1256 (2016).
Google Scholar
Shearer, M. J. Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev. 23, 49–59 (2009).
Google Scholar
Stock, M. & Schett, G. Vitamin K-dependent proteins in skeletal development and disease. Int. J. Mol. Sci. 22, 9328 (2021).
Google Scholar
Wen, L. P., Chen, J. P., Duan, L. L. & Li, S. Z. Vitamin K-dependent proteins involved in bone and cardiovascular health. Mol. Med. Rep. 18, 3–15 (2018).
Google Scholar
Furie, B. C. et al. The γ-carboxylation recognition site is sufficient to direct vitamin K-dependent carboxylation on all adjacent glutamate-rich region of thrombin in a propeptide–thrombin chimera. J. Biol. Chem. 272, 28258–28262 (1997).
Google Scholar
Jorgensen, M. J. et al. Recognition site directing vitamin K-dependent γ-carboxylation resides on the propeptide of factor-IX. Cell 48, 185–191 (1987).
Google Scholar
Freedman, S. J., Furie, B. C., Furie, B. & Baleja, J. D. Structure of the calcium ion-bound γ-carboxyglutamic acid-rich domain of factor-IX. Biochemistry 34, 12126–12137 (1995).
Google Scholar
Spyropoulos, A. C., Hayth, K. A. & Jenkins, P. Anticoagulation with anisindione in a patient with a warfarin-induced skin eruption. Pharmacotherapy 23, 533–536 (2003).
Google Scholar
Watzka, M. et al. Bleeding and non-bleeding phenotypes in patients with gene mutations. Thromb. Res. 134, 856–865 (2014).
Google Scholar
Tie, J., Wu, S. M., Jin, D. Y., Nicchitta, C. V. & Stafford, D. W. A topological study of the human γ-glutamyl carboxylase. Blood 96, 973–978 (2000).
Google Scholar
Tie, J. K. et al. Characterization of vitamin K-dependent carboxylase mutations that cause bleeding and nonbleeding disorders. Blood 127, 1847–1855 (2016).
Google Scholar
Tie, J. K. et al. Determination of disulfide bond assignment of human vitamin K-dependent γ-glutamyl carboxylase by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. J. Biol. Chem. 278, 45468–45475 (2003).
Google Scholar
Holm, L., Laiho, A., Törönen, P. & Salgado, M. DALI shines a light on remote homologs: one hundred discoveries. Protein Sci. 32, e4519 (2023).
Google Scholar
Wu, S. M., Mutucumarana, V. P., Geromanos, S. & Stafford, D. W. The propeptide binding site of the bovine γ-glutamyl carboxylase. J. Biol. Chem. 272, 11718–11722 (1997).
Google Scholar
Hoang, Q. Q., Sicheri, F., Howard, A. J. & Yang, D. S. C. Bone recognition mechanism of porcine osteocalcin from crystal structure. Nature 425, 977–980 (2003).
Google Scholar
Lin, P. J. et al. The putative vitamin K-dependent γ-glutamyl carboxylase internal propeptide appears to be the propeptide binding site. J. Biol. Chem. 277, 28584–28591 (2002).
Google Scholar
Hao, Z. Y. et al. γ-Glutamyl carboxylase mutations differentially affect the biological function of vitamin K dependent proteins. Blood 137, 533–543 (2021).
Google Scholar
Parker, C. H. et al. A conformational investigation of propeptide binding to the integral membrane protein γ-glutamyl carboxylase using nanodisc hydrogen exchange mass spectrometry. Biochemistry 53, 1511–1520 (2014).
Google Scholar
Mutucumarana, V. P., Acher, F., Straight, D. L., Jin, D. Y. & Stafford, D. W. A conserved region of human vitamin K-dependent carboxylase between residues 393 and 404 is important for its interaction with the glutamate substrate. J. Biol. Chem. 278, 46488–46493 (2003).
Google Scholar
Rishavy, M. A. & Berkner, K. L. Insight into the coupling mechanism of the vitamin K-dependent carboxylase: mutation of histidine 160 disrupts glutamic acid carbanion formation and efficient coupling of vitamin K epoxidation to glutamic acid carboxylation. Biochemistry 47, 9836–9846 (2008).
Google Scholar
Rishavy, M. A. et al. Bronsted analysis reveals Lys218 as the carboxylase active site base that deprotonates vitamin K hydroquinone to initiate vitamin K-dependent protein carboxylation. Biochemistry 45, 13239–13248 (2006).
Google Scholar
Rishavy, M. A. et al. A new model for vitamin K-dependent carboxylation: the catalytic base that deprotonates vitamin K hydroquinone is not Cys but an activated amine. Proc. Natl Acad. Sci. USA 101, 13732–13737 (2004).
Google Scholar
Mosley, S. T., Brown, M. S., Anderson, R. G. W. & Goldstein, J. L. Mutant clone of Chinese hamster ovary cells lacking 3-hydroxy-3-methylglutaryl coenzyme A reductase. J. Biol. Chem. 258, 3875–3881 (1983).
Google Scholar
Goldstein, J. L. & Brown, M. S. Regulation of the mevalonate pathway. Nature 343, 425–430 (1990).
Google Scholar
Metherall, J. E., Goldstein, J. L., Luskey, K. L. & Brown, M. S. Loss of transcriptional repression of three sterol-regulated genes in mutant hamster cells. J. Biol. Chem. 264, 15634–15641 (1989).
Google Scholar
Yang, T. et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110, 489–500 (2002).
Google Scholar
Qi, X., Friedberg, L., De Bose-Boyd, R., Long, T. & Li, X. Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling. Nat. Chem. Biol. 16, 1368–1375 (2020).
Google Scholar
Dowd, P., Hershline, R., Ham, S. W. & Naganathan, S. Vitamin K and energy transduction—a base strength amplification mechanism. Science 269, 1684–1691 (1995).
Google Scholar
Berkner, K. L. & Pudota, B. N. Vitamin K-dependent carboxylation of the carboxylase. Proc. Natl Acad. Sci. USA 95, 466–471 (1998).
Google Scholar
Hallgren, K. W., Zhang, D., Kinter, M., Willard, B. & Berkner, K. L. Methylation of γ-carboxylated Glu (Gla) allows detection by liquid chromatography–mass spectrometry and the identification of Gla residues in the γ-glutamyl carboxylase. J. Proteome Res. 12, 2365–2374 (2013).
Google Scholar
de Boer-van den Berg, M. A., Thijssen, H. H. & Vermeer, C. The in vivo effects of acenocoumarol, phenprocoumon and warfarin on vitamin K epoxide reductase and vitamin K-dependent carboxylase in various tissues of the rat. Biochim. Biophys. Acta 884, 150–157 (1986).
Google Scholar
Tie, J. K., Jin, D. Y., Straight, D. L. & Stafford, D. W. Functional study of the vitamin K cycle in mammalian cells. Blood 117, 2967–2974 (2011).
Google Scholar
Di Minno, A. et al. Old and new oral anticoagulants: food, herbal medicines and drug interactions. Blood Rev. 31, 193–203 (2017).
Google Scholar
Goldstein, J. L. & Brown, M. S. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161, 161–172 (2015).
Google Scholar
Undas, A., Brummel-Ziedins, K. E. & Mann, K. G. Anticoagulant effects of statins and their clinical implications. Thromb. Haemost. 111, 392–400 (2014).
Google Scholar
Jiang, S. Y. et al. Schnyder corneal dystrophy-associated UBIAD1 mutations cause corneal cholesterol accumulation by stabilizing HMG-CoA reductase. PLoS Genet. 15, e1008289 (2019).
Google Scholar
Schumacher, M. M., Elsabrouty, R., Seemann, J., Jo, Y. & DeBose-Boyd, R. A. The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase. eLife 4, e05560 (2015).
Google Scholar
Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331–332 (2017).
Google Scholar
Zivanov, J. et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. eLife 7, e42166 (2018).
Google Scholar
Rohou, A. & Grigorieff, N. CTFFIND4: fast and accurate defocus estimation from electron micrographs. J. Struct. Biol. 192, 216–221 (2015).
Google Scholar
Wagner, T. et al. SPHIRE-crYOLO is a fast and accurate fully automated particle picker for cryo-EM. Commun. Biol. 2, 218 (2019).
Google Scholar
Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017).
Google Scholar
Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).
Google Scholar
Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).
Google Scholar
Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).
Google Scholar
Pettersen, E. F. et al. UCSF chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).
Google Scholar
Pettersen, E. F. et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci. 30, 70–82 (2021).
Google Scholar
McFarlane, M. R. et al. Scap is required for sterol synthesis and crypt growth in intestinal mucosa. J. Lipid Res. 56, 1560–1571 (2015).
Google Scholar
Li, H., Robertson, A. D. & Jensen, J. H. Very fast empirical prediction and rationalization of protein pK values. Proteins 61, 704–721 (2005).
Google Scholar
Brooks, B. R. et al. Charmm—a program for macromolecular energy, minimization, and dynamics calculations. J. Comput. Chem. 4, 187–217 (1983).
Google Scholar
Vanommeslaeghe, K. et al. CHARMM general force field: a force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J. Comput. Chem. 31, 671–690 (2010).
Google Scholar
Jo, S., Kim, T., Iyer, V. G. & Im, W. CHARMM-GUI: a web-based graphical user interface for CHARMM. J. Comput. Chem. 29, 1859–1865 (2008).
Google Scholar
Lomize, M. A., Lomize, A. L., Pogozheva, I. D. & Mosberg, H. I. OPM: orientations of proteins in membranes database. Bioinformatics 22, 623–625 (2006).
Google Scholar
Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W. & Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926–935 (1983).
Google Scholar
Phillips, J. C. et al. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26, 1781–1802 (2005).
Google Scholar
MacKerell, A. D. et al. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 102, 3586–3616 (1998).
Google Scholar
Essmann, U. et al. A smooth particle mesh Ewald method. J. Chem. Phys. 103, 8577–8593 (1995).
Google Scholar
Elghobashi-Meinhardt, N. Structure and mechanism of vitamin K-dependent gamma-glutamyl carboxylase (GGCX) MD simulation data. Zenodo https://doi.org/10.5281/zenodo.14150943 (2024).