9BUM

Structure of gamma-glutamyl carboxylase (GGCX)

9BUM の概要

• エントリーDOI: 10.2210/pdb9bum/pdb
• EMDBエントリー: 44912
• 分子名称: Vitamin K-dependent gamma-carboxylase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, CHOLESTEROL (3 entities in total)
• 機能のキーワード: vitamin k cycle, membrane protein, lyase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 89463.66

構造登録者

Wang, R.,Qi, X. (登録日: 2024-05-17, 公開日: 2025-01-29, 最終更新日: 2025-03-26)

主引用文献

Wang, R.,Chen, B.,Elghobashi-Meinhardt, N.,Tie, J.K.,Ayala, A.,Zhou, N.,Qi, X.
Structure and mechanism of vitamin-K-dependent gamma-glutamyl carboxylase.
Nature, 639:808-815, 2025

PubMed 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 diseases. 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.

PubMed: 39880952
DOI: 10.1038/s41586-024-08484-9

実験手法

ELECTRON MICROSCOPY (3.63 Å)