Molecular basis of vitamin-K-driven γ-carboxylation at the membrane interface

Qing Cao, Aaron Ammerman, Mierxiati Saimi, Zongtao Lin, Guomin Shen, Huaping Chen, Jie Sun, Mengqi Chai, Shixuan Liu, Fong-Fu Hsu, Andrzej M. Krezel, Michael L. Gross, Jinbin Xu, Benjamin A. Garcia, Bin Liu () and Weikai Li ()
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Qing Cao: Washington University School of Medicine
Aaron Ammerman: Washington University School of Medicine
Mierxiati Saimi: Washington University School of Medicine
Zongtao Lin: Washington University School of Medicine
Guomin Shen: Washington University School of Medicine
Huaping Chen: Washington University School of Medicine
Jie Sun: Washington University
Mengqi Chai: Washington University
Shixuan Liu: Washington University School of Medicine
Fong-Fu Hsu: Washington University School of Medicine
Andrzej M. Krezel: Washington University School of Medicine
Michael L. Gross: Washington University
Jinbin Xu: Washington University School of Medicine
Benjamin A. Garcia: Washington University School of Medicine
Bin Liu: University of Minnesota
Weikai Li: Washington University School of Medicine

Nature, 2025, vol. 639, issue 8055, 816-824

Abstract: Abstract The γ-carboxylation of glutamate residues enables Ca2+-mediated membrane assembly of protein complexes that support broad physiological functions, including haemostasis, calcium homeostasis, immune response and endocrine regulation1–4. Modulating γ-carboxylation levels provides prevalent treatments for haemorrhagic and thromboembolic diseases5. This unique post-translational modification requires vitamin K hydroquinone (KH2) to drive highly demanding reactions6 catalysed by the membrane-integrated γ-carboxylase (VKGC). Here, to decipher the underlying mechanisms, we determined cryo-electron microscopy structures of human VKGC in unbound form, with KH2 and four haemostatic and non-haemostatic proteins possessing propeptides and glutamate-rich domains in different carboxylation states. VKGC recognizes substrate proteins through knob-and-hole interactions with propeptides, thereby bringing tethered glutamate-containing segments for processive carboxylation within a large chamber that provides steric control. Propeptide binding also triggers a global conformational change to signal VKGC activation. Through sequential deprotonation and KH2 epoxidation, VKGC generates a free hydroxide ion as an exceptionally strong base that is required to deprotonate the γ-carbon of glutamate for CO2 addition. The diffusion of this superbase—protected and guided by a sealed hydrophobic tunnel—elegantly resolves the challenge of coupling KH2 epoxidation to γ-carboxylation across the membrane interface. These structural insights and extensive functional experiments advance membrane enzymology and propel the development of treatments for γ-carboxylation disorders.

Date: 2025
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DOI: 10.1038/s41586-025-08648-1

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