近日，美国华盛顿大学医学院栗卫凯及其研究团队提出了对维生素K依赖性骨钙素γ-羧化的结构见解。2025年9月2日，国际知名学术期刊《细胞研究》发表了这一成果。

为了了解潜在的分子机制，研究组测定了骨钙素携带天然前肽或高亲和力变体在不同羧化状态下的VKGC的冷冻电镜结构。这些结构揭示了VKGC中的一个大腔室，该腔室将未羧化和部分羧化的骨钙素维持在部分展开的构象中，允许其富含谷氨酸的区域和C端螺旋在多个位点与VKGC结合。这一成熟区域与低亲和力前肽结合可有效刺激VKGC活性，类似于高亲和力前肽，其区别仅在于紧密配合的相互作用。

然而，低亲和力的前肽使骨钙素在低维生素K水平下易于羧化，从而作为可识别的生物标志物。总的来说，他们的研究揭示了骨钙素与VKGC的独特相互作用，并为设计针对骨钙素相关骨和代谢紊乱的治疗策略提供了框架。

据悉，骨钙素的γ-羧化状态决定了其在骨矿化或全身代谢中的基本功能，是骨骼健康和维生素K营养的重要生物标志物。这种谷氨酸残基的翻译后修饰是由膜嵌入的维生素k依赖性γ-羧化酶（VKGC）催化的，该酶通常通过紧密结合的前肽来识别蛋白质底物，从而触发γ-羧化。然而，骨钙素前肽对VKGC的亲和力可以忽略不计。

附：英文原文

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

Author: Cao, Qing, Fan, Jianjun, Ammerman, Aaron, Awasthi, Samjhana, Lin, Zongtao, Mierxiati, Saimi, Chen, Huaping, Xu, Jinbin, Garcia, Benjamin A., Liu, Bin, Li, Weikai

Issue&Volume: 2025-09-02

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.

DOI: 10.1038/s41422-025-01161-0

Source: https://www.nature.com/articles/s41422-025-01161-0