Structure and mechanism of vitamin-K-dependent γ-glutamyl carboxylase
成果类型：
Article
署名作者：
Wang, Rong; Chen, Baozhi; Elghobashi-Meinhardt, Nadia; Tie, Jian-Ke; Ayala, Alyssa; Zhou, Ning; Qi, Xiaofeng
署名单位：
University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University College Dublin; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of Texas System; University of Texas Southwestern Medical Center
刊物名称：
Nature
ISSN/ISSBN：
0028-0908
DOI：
10.1038/s41586-024-08484-9
发表日期：
2025-03-20
关键词：
propeptide binding
membrane-protein
recognition site
mutations
DYNAMICS
warfarin
base
bone
hydroquinone
cholesterol
摘要：
gamma-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 gamma-carboxyglutamate residues in VK-dependent proteins (VDPs), which are involved in various essential biological processes and diseases1, 2-3. 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 gamma-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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