Volume 35, No 10, Oct 2025

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 35 Issue 10, October 2025: 735-749

ORIGINAL ARTICLES

Structural insights into the vitamin K-dependent γ-carboxylation of osteocalcin

Qing Cao^1,† , Jianjun Fan^1,† , Aaron Ammerman¹ , Samjhana Awasthi¹ , Zongtao Lin¹ , Saimi Mierxiati¹ , Huaping Chen² , Jinbin Xu² , Benjamin A. Garcia¹ , Bin Liu^3,* , Weikai Li^1,*

¹Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA
²Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA
³The Hormel Institute, University of Minnesota, Austin, MN, USA
^†These authors contributed equally: Qing Cao, Jianjun Fan
Correspondence: Bin Liu(liu00794@umn.edu)Weikai Li(weikai@wustl.edu)

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.

https://doi.org/10.1038/s41422-025-01161-0

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