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Publication Abstract from PubMed

The gamma-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 gamma-carboxylase (VKGC), which typically recognizes protein substrates through their tightly bound propeptide that triggers gamma-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.

Structural insights into the vitamin K-dependent gamma-carboxylation of osteocalcin.,Cao Q, Fan J, Ammerman A, Awasthi S, Lin Z, Mierxiati S, Chen H, Xu J, Garcia BA, Liu B, Li W Cell Res. 2025 Oct;35(10):735-749. doi: 10.1038/s41422-025-01161-0. Epub 2025 Sep , 2. PMID:40890294^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.