9MQC

Vitamin K-dependent gamma-carboxylase with Osteocalcin (mutant) and vitamin K hydroquinone

This is a non-PDB format compatible entry.

Summary for 9MQC

• Entry DOI: 10.2210/pdb9mqc/pdb
• EMDB information: 48520
• Descriptor: Vitamin K-dependent gamma-carboxylase, Osteocalcin, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: ggcx, vkgc, vitamin k, vkcfd, hemophilia b, warfarin, carboxylation, blood coagulation, calcium homeostasis, osteocalcin, membrane protein, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 102150.59

Authors

Li, W.,Liu, B.,Cao, Q. (deposition date: 2025-01-02, release date: 2025-10-08)

Primary citation

Cao, Q.,Fan, J.,Ammerman, A.,Awasthi, S.,Lin, Z.,Mierxiati, S.,Chen, H.,Xu, J.,Garcia, B.A.,Liu, B.,Li, W.
Structural insights into the vitamin K-dependent gamma-carboxylation of osteocalcin.
Cell Res., 35:735-749, 2025

PubMed Abstract: The γ-carboxylation state of osteocalcin determines its essential functions in bone mineralization or systemic metabolism and serves as a prominent biomarker for bone health and vitamin K nutrition. This post-translational modification of glutamate residues is catalyzed by the membrane-embedded vitamin K-dependent γ-carboxylase (VKGC), which typically recognizes protein substrates through their tightly bound propeptide that triggers γ-carboxylation. However, the osteocalcin propeptide exhibits negligible affinity for VKGC. To understand the underlying molecular mechanism, we determined the cryo-electron microscopy structures of VKGC with osteocalcin carrying a native propeptide or a high-affinity variant at different carboxylation states. The structures reveal a large chamber in VKGC that maintains uncarboxylated and partially carboxylated osteocalcin in partially unfolded conformations, allowing their glutamate-rich region and C-terminal helices to engage with VKGC at multiple sites. Binding of this mature region together with the low-affinity propeptide effectively stimulates VKGC activity, similar to high-affinity propeptides that differ only in closely fitting interactions. However, the low-affinity propeptide renders osteocalcin prone to undercarboxylation at low vitamin K levels, thereby serving as a discernible biomarker. Overall, our studies reveal the unique interaction of osteocalcin with VKGC and provide a framework for designing therapeutic strategies targeting osteocalcin-related bone and metabolic disorders.

PubMed: 40890294
DOI: 10.1038/s41422-025-01161-0

Experimental method

ELECTRON MICROSCOPY (3.13 Å)