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).
Furie, B., Bouchard, B. A. & Furie, B. C. Vitamin K-dependent biosynthesis of γ-carboxyglutamic acid. Blood 93, 1798–1808 (1999).
Berkner, K. L. Vitamin K-dependent carboxylation. Vitam. Horm. 78, 131–156 (2008).
Mladenka, P. et al. Vitamin K—sources, physiological role, kinetics, deficiency, detection, therapeutic use, and toxicity. Nutr. Rev. 80, 677–698 (2022).
Stafford, D. W. The vitamin K cycle. J. Thromb. Haemost. 3, 1873–1878 (2005).
Shearer, M. J. & Okano, T. Key pathways and regulators of vitamin K function and intermediary metabolism. Annu. Rev. Nutr. 38, 127–151 (2018).
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).
Li, T. et al. Identification of the gene for vitamin K epoxide reductase. Nature 427, 541–544 (2004).
Rost, S. et al. Mutations in cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427, 537–541 (2004).
Furie, B. & Furie, B. C. The molecular basis of blood coagulation. Cell 53, 505–518 (1988).
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).
Karsenty, G. & Olson, E. N. Bone and muscle endocrine functions: unexpected paradigms of inter-organ communication. Cell 164, 1248–1256 (2016).
Shearer, M. J. Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev. 23, 49–59 (2009).
Stock, M. & Schett, G. Vitamin K-dependent proteins in skeletal development and disease. Int. J. Mol. Sci. 22, 9328 (2021).
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).
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).
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).
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).
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).
Watzka, M. et al. Bleeding and non-bleeding phenotypes in patients with gene mutations. Thromb. Res. 134, 856–865 (2014).
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).
Tie, J. K. et al. Characterization of vitamin K-dependent carboxylase mutations that cause bleeding and nonbleeding disorders. Blood 127, 1847–1855 (2016).
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).
Holm, L., Laiho, A., Törönen, P. & Salgado, M. DALI shines a light on remote homologs: one hundred discoveries. Protein Sci. 32, e4519 (2023).
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).
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).
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).
Hao, Z. Y. et al. γ-Glutamyl carboxylase mutations differentially affect the biological function of vitamin K dependent proteins. Blood 137, 533–543 (2021).
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).
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).
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).
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).
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).
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).
Goldstein, J. L. & Brown, M. S. Regulation of the mevalonate pathway. Nature 343, 425–430 (1990).
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).
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).
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).
Dowd, P., Hershline, R., Ham, S. W. & Naganathan, S. Vitamin K and energy transduction—a base strength amplification mechanism. Science 269, 1684–1691 (1995).
Berkner, K. L. & Pudota, B. N. Vitamin K-dependent carboxylation of the carboxylase. Proc. Natl Acad. Sci. USA 95, 466–471 (1998).
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).
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).
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).
Di Minno, A. et al. Old and new oral anticoagulants: food, herbal medicines and drug interactions. Blood Rev. 31, 193–203 (2017).
Goldstein, J. L. & Brown, M. S. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161, 161–172 (2015).
Undas, A., Brummel-Ziedins, K. E. & Mann, K. G. Anticoagulant effects of statins and their clinical implications. Thromb. Haemost. 111, 392–400 (2014).
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).
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).
Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331–332 (2017).
Zivanov, J. et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. eLife 7, e42166 (2018).
Rohou, A. & Grigorieff, N. CTFFIND4: fast and accurate defocus estimation from electron micrographs. J. Struct. Biol. 192, 216–221 (2015).
Wagner, T. et al. SPHIRE-crYOLO is a fast and accurate fully automated particle picker for cryo-EM. Commun. Biol. 2, 218 (2019).
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).
Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).
Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).
Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).
Pettersen, E. F. et al. UCSF chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).
Pettersen, E. F. et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci. 30, 70–82 (2021).
McFarlane, M. R. et al. Scap is required for sterol synthesis and crypt growth in intestinal mucosa. J. Lipid Res. 56, 1560–1571 (2015).
Li, H., Robertson, A. D. & Jensen, J. H. Very fast empirical prediction and rationalization of protein pK values. Proteins 61, 704–721 (2005).
Brooks, B. R. et al. Charmm—a program for macromolecular energy, minimization, and dynamics calculations. J. Comput. Chem. 4, 187–217 (1983).
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).
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).
Lomize, M. A., Lomize, A. L., Pogozheva, I. D. & Mosberg, H. I. OPM: orientations of proteins in membranes database. Bioinformatics 22, 623–625 (2006).
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).
Phillips, J. C. et al. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26, 1781–1802 (2005).
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).
Essmann, U. et al. A smooth particle mesh Ewald method. J. Chem. Phys. 103, 8577–8593 (1995).
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).