Structural insight into bicarbonate-mediated carboxylation by human vitamin K-dependent carboxylase

作者：Ke Wu, Zheng Wang, Deqiang Yao, Shaobai Li, Xiaozhu Wang, Yuanyuan Zhang, Cao Mi, Yafeng Shen, Shunpeng Xing, Jian Wu, Ming Lei, Pengfei Lan · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-65488-3 · 被引用次数：2 · 研究领域：Vitamin K Research Studies、Biotin and Related Studies、Alcoholism and Thiamine Deficiency

Vitamin K-dependent (VKD) carboxylation, mediated by γ-glutamyl carboxylase (GGCX), is essential for the maturation of VKD proteins involved in critical physiological processes such as blood clotting, vascular calcification and bone metabolism. Here, we present cryo-electron microscopic structures of human GGCX alone and in complex with VKD proteins, vitamin K, and inhibitor anisindione. GGCX specifically recognizes diverse VKD substrates through high-affinity propeptide binding, while substrates like osteocalcin utilize a secondary exosite to enhance interaction. GGCX employs a conserved dipeptide anchoring mechanism that ensures processive carboxylation of glutamate residues. GGCX undergoes allosteric conformational changes that enable coordinated binding of vitamin K and glutamate substrates, facilitating the catalytic process. Additionally, we reveal a bicarbonate-mediated CO₂ capture mechanism that is conserved across bacterial and eukaryotic species, suggesting that this strategy for CO₂ utilization is both ancient and universal. Our findings lay the foundation for developing targeted anticoagulant drugs and innovative enzymatic CO₂ fixation strategies. Vitamin K-dependent carboxylation is vital for human health. Here, authors present cryo-EM structures of the relevant γ-glutamyl carboxylase, uncovering substrate recognition, processive modification, and a bicarbonate-mediated CO₂ fixation mechanism.