9BVQ

Vitamin K-dependent gamma-carboxylase with TMG2 propeptide and glutamate-rich region

Summary for 9BVQ

• Entry DOI: 10.2210/pdb9bvq/pdb
• EMDB information: 44941
• Descriptor: Vitamin K-dependent gamma-carboxylase, Transmembrane gamma-carboxyglutamic acid protein 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: ggcx, vkgc, vitamin k, vkcfd, hemophilia b, warfarin, carboxylation, blood coagulaton, calcium homeostasis, tmg, membrane protein, gla, lyase-substrate complex, lyase/substrate
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 101426.18

Authors

Li, W.,Liu, B.,Cao, Q. (deposition date: 2024-05-20, release date: 2025-01-22, Last modification date: 2025-03-26)

Primary citation

Cao, Q.,Ammerman, A.,Saimi, M.,Lin, Z.,Shen, G.,Chen, H.,Sun, J.,Chai, M.,Liu, S.,Hsu, F.F.,Krezel, A.M.,Gross, M.L.,Xu, J.,Garcia, B.A.,Liu, B.,Li, W.
Molecular basis of vitamin-K-driven gamma-carboxylation at the membrane interface.
Nature, 639:816-824, 2025

PubMed Abstract: The γ-carboxylation of glutamate residues enables Ca-mediated membrane assembly of protein complexes that support broad physiological functions including hemostasis, calcium homeostasis, immune response, and endocrine regulation. Modulating γ-carboxylation level provides prevalent treatments for hemorrhagic and thromboembolic diseases. This unique posttranslational modification requires vitamin K hydroquinone (KH) to drive highly demanding reactions catalyzed by the membrane-integrated γ-carboxylase (VKGC). To decipher underlying mechanisms, we determined cryo-electron microscopy structures of human VKGC in unbound form, with KH and four hemostatic and non-hemostatic proteins possessing propeptides and glutamate-rich domains in different carboxylation states. VKGC recognizes substrate proteins via 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 KH epoxidation, VKGC generates free hydroxide ion as an exceptionally strong base required to deprotonate the γ-carbon of glutamate for CO addition. The diffusion of this superbase, protected and guided by a sealed hydrophobic tunnel, elegantly resolves the challenge of coupling KH epoxidation to γ-carboxylation across the membrane interface. These structural insights and extensive functional experiments advance membrane enzymology and propel the development of novel treatments for γ-carboxylation disorders.

PubMed: 39880037
DOI: 10.1038/s41586-025-08648-1

Experimental method

ELECTRON MICROSCOPY (3.3 Å)