EMD-44912

Single-particle
3.63 Å
EMD-44912 Deposition: 17/05/2024
Map released: 29/01/2025
Last modified: 12/02/2025
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-44912

Structure of r-glutamyl carboxylase (GGCX)

EMD-44912

Single-particle
3.63 Å
EMD-44912 Deposition: 17/05/2024
Map released: 29/01/2025
Last modified: 12/02/2025
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: GGCX protein
Fitted models: 9bum

Deposition Authors: Wang R , Qi X
Structure and mechanism of vitamin-K-dependent gamma-glutamyl carboxylase.
PUBMED: 39880952
DOI: doi:10.1038/s41586-024-08484-9
ISSN: 1476-4687
ASTM: NATUAS
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.