The carboxylation status of osteocalcin has important consequences for its structure and dynamics.
The carboxylation status of osteocalcin has important consequences for its structure and dynamics.
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DOI：
10.1016/j.bbagen.2020.129809
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Smith JC
中科院分区：
文献类型：
--
作者：
Kapoor K;Pi M;Nishimoto SK;Quarles LD;Baudry J;Smith JC
骨钙素（OCN）的羧化状态不仅影响骨的形成和结构，而且具有重要的内分泌功能，影响能量代谢和消耗。本文研究了谷氨酸残基的γ-羧化在OCN结构-动力学-功能关系中的作用。三种形式的OCN，差异羧化的Glu-17，21和24个残基，沿着与突变形式的OCN携带Glu/Ala突变，建模和模拟使用分子动力学（MD）模拟在钙离子的存在下。OCN的全球构象动力学的表征，描述在其3-螺旋结构域内的取向变化，突出了大的非羧基化骨钙素（nOCN）的结构变化。相比之下，二羧化的OCN（bOCN）和三羧化的（tOCN）物种，显示相对刚性的三级结构，与大多数区域的动力学强烈相关。计算的bOcn和tOcn的径向分布函数显示了羧化谷氨酸（γGlu）残基周围钙离子分布的长程有序性，可能在促进这些Ocn的稳定性方面发挥重要作用。此外，观察到相同的钙离子与相邻的γGlu配位，更好地屏蔽它们的负电荷，从而比在nOcn的情况下观察到的单配位钙离子更稳定这些系统。还发现bOCN表现出更加螺旋的C末端结构，已被证明可以激活其细胞受体GPRC 6A，这凸显了OCN羧化在调节活性C末端的稳定性和结合潜力方面的变构作用。OCN的羧化状态及其钙配位似乎对OCN结构和动力学具有直接影响，可能导致OCN生物功能的已知差异。Ocn序列或其羧化状态的修饰可能为开发针对其细胞受体GPRC 6A的高亲和力肽提供蓝图，具有治疗代谢性疾病的治疗潜力。
The carboxylation status of Osteocalcin (Ocn) not only influences formation and structure in bones but also has important endocrine functions affecting energy metabolism and expenditure. In this study, the role of γ-carboxylation of the glutamate residues in the structure-dynamics-function relationship in Ocn is investigated. Three forms of Ocn, differentially carboxylated at the Glu-17, 21 and 24 residues, along with a mutated form of Ocn carrying Glu/Ala mutations, are modeled and simulated using molecular dynamics (MD) simulation in the presence of calcium ions. Characterization of the global conformational dynamics of Ocn, described in terms of the orientational variations within its 3-helical domain, highlights large structural variations in the non-carboxylated osteocalcin (nOcn). The bi-carboxylated Ocn (bOcn) and tri-carboxylated (tOcn) species, in contrast, display relatively rigid tertiary structures, with the dynamics of most regions strongly correlated. Radial distribution functions calculated for both bOcn and tOcn show long-range ordering of the calcium ion distribution around the carboxylated glutamate (γGlu) residues, likely playing an important role in promoting stability of these Ocns. Additionally, the same calcium ions are observed to coordinate with neighboring γGlu, better shielding their negative charges and in turn stabilizing these systems more than do the singly coordinating calcium ions observed in the case of nOcn. bOcn is also found to exhibit a more helical C-terminal structure, that has been shown to activate its cellular receptor GPRC6A, highlighting the allosteric role of Ocn carboxylation in modulating the stability and binding potential of the active C-terminal. The carboxylation status of Ocn as well and its calcium coordination appear to have a direct influence on Ocn structure and dynamics, possibly leading to the known differences in Ocn biological function. Modification of Ocn sequence or its carboxylation state may provide the blueprint for developing high-affinity peptides targeting its cellular receptor GPRC6A, with therapeutic potential for treatment of metabolic disorders.
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影响因子：
64.5
作者：
Ferron M;Wei J;Yoshizawa T;Del Fattore A;DePinho RA;Teti A;Ducy P;Karsenty G
通讯作者：
Karsenty G
影响因子：
24
作者：
Goessl, Mario;Moedder, Ulrike I.;Atkinson, Elizabeth J.;Lerman, Amir;Khosla, Sundeep
通讯作者：
Khosla, Sundeep
DOI：
10.1002/prot.340230412
发表时间：
1995-12-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Frishman, D;Argos, P
通讯作者：
Argos, P
影响因子：
2.7
作者：
HAUSCHKA, PV;REID, ML
通讯作者：
REID, ML
DOI：
10.1073/pnas.72.10.3925
发表时间：
1975-01-01
影响因子：
11.1
作者：
HAUSCHKA, PV;LIAN, JB;GALLOP, PM
通讯作者：
GALLOP, PM