摘要
钙稳态是在正常细胞里需要严格控制的基本的生理过程。通过钙结合或钙传感能力的丢失,钙稳态失调可能在阿尔茨海默病(AD)和其他疾病的发病中起关键作用。钙结合蛋白(CB-D28K)由六个EF-手型钙结合蛋白组成,其中四个可以结合Ca2+,与AD相关的钙失调关联。在这项研究中,为了理解EF-手型潜在的功能性和非功能性的之间的结构变化,运用分子对接和分子动力学计算,完善蛋白质的数据基础模型。分子模拟计算改善了模拟的蛋白质结构:所有的手型形成了螺旋-环-螺旋序列,四个功能性的手型形成了最典型的相互作用。蛋白质也可以结合Zn2+,可能改变Ca2+结合能力。计算锌结合蛋白的结构分析显示只有一半的正确的EF-手型形成典型的有环形残基的Ca2+的相互作用。这些结果对理解钙代谢异常以及对AD和其他中枢神经系统疾病的新的治疗策略的发展,或了解在脑损伤条件下哪里钙稳态被破坏有重要意义。
关键词: 阿尔茨海默病,钙结合蛋白D28k,钙结合蛋白,钙稳态,分子动力学模拟,锌。
Current Alzheimer Research
Title:Protein Structural Analysis of Calbindin D28k Function and Dysregulation: Potential Competition Between Ca2+ and Zn2+
Volume: 13 Issue: 7
Author(s): Sara Ibrahim Omar, Benedict C. Albensi, Kathleen M. Gough
Affiliation:
关键词: 阿尔茨海默病,钙结合蛋白D28k,钙结合蛋白,钙稳态,分子动力学模拟,锌。
摘要: Calcium homeostasis is an essential physiological process requiring tight control in the normal cell. The dysregulation of calcium homeostasis may play a key role in the onset of Alzheimer’s disease (AD) and other disorders, whether through the loss of calcium binding or calcium sensing capacity. Calbindin D28k (CB-D28k), a calcium binding protein composed of six EF-hands, four of which can bind Ca2+, has been implicated in AD-related calcium dysregulation. In this study, docking and molecular dynamics calculations were employed to refine the protein data base model in order to understand the underlying structural variations between functional and non-functional EF-hands. Molecular modeling calculations improved the modelled protein structure: helix-loop-helix sequences were formed in all hands and most canonical interactions were formed in the four functional hands. The protein can also bind Zn2+, potentially altering the Ca2+ binding capability. Analysis of calculated structures of Zn2+ bound protein showed that only half of the correct EF-hand canonical interactions of Ca2+ were formed with loop residues. These results have important implications for the understanding of calcium dysregulation as well as for the development of novel therapeutic strategies in AD and other central nervous system disease processes, or in conditions of brain injury where calcium homeostasis is compromised.
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Cite this article as:
Sara Ibrahim Omar, Benedict C. Albensi, Kathleen M. Gough , Protein Structural Analysis of Calbindin D28k Function and Dysregulation: Potential Competition Between Ca2+ and Zn2+, Current Alzheimer Research 2016; 13 (7) . https://dx.doi.org/10.2174/1567205013666160310144100
DOI https://dx.doi.org/10.2174/1567205013666160310144100 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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