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

Ke Wu, Zheng Wang, Deqiang Yao, Shaobai Li, Xiaozhu Wang, Yuanyuan Zhang, Mi Cao, Yafeng Shen, Shunpeng Xing, Jian Wu, Ming Lei () and Pengfei Lan ()
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Ke Wu: Shanghai Jiao Tong University School of Medicine, Institute of Aging and Tissue Regeneration, Renji Hospital
Zheng Wang: Shanghai Jiao Tong University School of Medicine, Institute of Aging and Tissue Regeneration, Renji Hospital
Deqiang Yao: Shanghai Jiao Tong University School of Medicine, Institute of Aging and Tissue Regeneration, Renji Hospital
Shaobai Li: Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Precision Medicine, Ninth People’s Hospital
Xiaozhu Wang: Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Precision Medicine, Ninth People’s Hospital
Yuanyuan Zhang: Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Precision Medicine, Ninth People’s Hospital
Mi Cao: Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Precision Medicine, Ninth People’s Hospital
Yafeng Shen: Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Precision Medicine, Ninth People’s Hospital
Shunpeng Xing: Shanghai Jiao Tong University School of Medicine, Department of Critical Care Medicine, Renji Hospital
Jian Wu: Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Precision Medicine, Ninth People’s Hospital
Ming Lei: Shanghai Jiao Tong University School of Medicine, Institute of Aging and Tissue Regeneration, Renji Hospital
Pengfei Lan: Shanghai Jiao Tong University School of Medicine, Institute of Aging and Tissue Regeneration, Renji Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65488-3

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