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

  • Nature. 2025 Mar;639(8055):808-815. doi: 10.1038/s41586-024-08484-9.
Rong Wang  1 ,  Baozhi Chen  2 ,  Nadia Elghobashi-Meinhardt  3 ,  Jian-Ke Tie  4 ,  Alyssa Ayala  2 ,  Ning Zhou  2 ,  Xiaofeng Qi  5  6
Affiliations
  • 1. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 3. School of Chemistry, University College Dublin, Dublin, Ireland.
  • 4. Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 5. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 6. Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA. [email protected].
PMID: 39880952 DOI: 10.1038/s41586-024-08484-9
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.

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