Structure and mechanism of vitamin-K-dependent γ-glutamyl carboxylase

Rong Wang, Baozhi Chen, Nadia Elghobashi-Meinhardt, Jian-Ke Tie, Alyssa Ayala, Ning Zhou and Xiaofeng Qi ()
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Rong Wang: University of Texas Southwestern Medical Center
Baozhi Chen: University of Texas Southwestern Medical Center
Nadia Elghobashi-Meinhardt: University College Dublin
Jian-Ke Tie: University of North Carolina at Chapel Hill
Alyssa Ayala: University of Texas Southwestern Medical Center
Ning Zhou: University of Texas Southwestern Medical Center
Xiaofeng Qi: University of Texas Southwestern Medical Center

Nature, 2025, vol. 639, issue 8055, 808-815

Abstract: Abstract γ-Glutamyl carboxylase (GGCX) is the sole identified enzyme that uses vitamin K (VK) as a cofactor in humans. This protein catalyses the oxidation of VK hydroquinone to convert specific glutamate residues to γ-carboxyglutamate residues in VK-dependent proteins (VDPs), which are involved in various essential biological processes and diseases1–3. However, the working mechanism of GGCX remains unclear. Here we report three cryogenic electron microscopy structures of human GGCX: in the apo state, bound to osteocalcin (a VDP) and bound to VK. The propeptide of the VDP binds to the lumenal domain of GGCX, which stabilizes transmembrane helices 6 and 7 of GGCX to create the VK-binding pocket. After binding of VK, residue Lys218 in GGCX mediates the oxidation of VK hydroxyquinone, which leads to the deprotonation of glutamate residues and the construction of γ-carboxyglutamate residues. Our structural observations and results from binding and cell biological assays and molecular dynamics simulations show that a cholesterol molecule interacts with the transmembrane helices of GGCX to regulate its protein levels in cells. Together, these results establish a link between cholesterol metabolism and VK-dependent pathways.

Date: 2025
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DOI: 10.1038/s41586-024-08484-9

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