Carboxylation-dependent conformational changes of human osteocalcin.
Carboxylation-dependent conformational changes of human osteocalcin.
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DOI：
10.2741/4270
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发表时间：
2014-06
期刊：
影响因子：
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通讯作者：
A. Cristiani;F. Maset;L. De Toni;D. Guidolin;Davide Sabbadin;G. Strapazzon;S. Moro;V. De Filippis;C. Foresta
中科院分区：
文献类型：
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作者：
A. Cristiani;F. Maset;L. De Toni;D. Guidolin;Davide Sabbadin;G. Strapazzon;S. Moro;V. De Filippis;C. Foresta
骨钙素（OCN）是一种主要由成骨细胞产生的小分子非胶原蛋白，在大多数脊椎动物的骨中高度表达。人OCN在位置17、21和24处含有多达三个γ-羧基谷氨酸（Gla-OCN）残基，其被认为增加钙结合强度，改善骨基质的机械性质。最近的研究表明，OCN也发挥重要的内分泌功能，影响能量代谢和男性生育能力。后一种效应似乎是由OCN的未羧基化形式（Glu-OCN）介导的。我们采用人类和小鼠OCN的完全羧化和未羧化的OCN形式的模型进行调查，通过使用圆二色性和分子动力学模拟，各自的构象特性和Ca 2+亲和力。发现Ca 2+结合在Glu-OCN和Gla-OCN中触发类似的构象转变，从无序结构到更紧凑/稳定的形式。值得注意的是，γ-羧化使OCN对Ca 2+的亲和力增加> 30倍，表明在生理条件下，Gla-OCN基本上是Ca 2+结合的，而Glu-OCN主要以无Ca 2+形式循环。
Osteocalcin (OCN) is a small noncollagenous protein mainly produced by osteoblasts and is highly represented in bones of most vertebrates. Human OCN contains up to three gamma-carboxyglutamic acid (Gla-OCN) residues at positions 17, 21 and 24 which are thought to increase calcium binding strength, improving mechanical properties of the bone matrix. Recent studies revealed that OCN exerts also important endocrine functions, affecting energy metabolism and male fertility. The latter effect seems to be mediated by the uncarboxylated form of OCN (Glu-OCN). We employed human and mouse OCN as models of fully carboxylated and uncarboxylated OCN forms to investigate, by the use of circular dichroism and molecular dynamics simulations, the respective conformational properties and Ca2+ affinity. Ca2+ binding was found to trigger a similar conformational transition in both Glu-OCN and Gla-OCN, from a disordered structure to a more compact/stable form. Notably, gamma-carboxylation increases the affinity of OCN for Ca2+ by > 30 fold suggesting that, in physiological conditions, Gla-OCN is essentially Ca2+-bound, whereas Glu-OCN circulates mainly in the Ca2+-free form.