Lipid-induced conformational switch of apolipophorin III
脂质诱导的载脂蛋白 III 构象转换
基本信息
- 批准号:6806133
- 负责人:
- 金额:$ 21.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-07-01 至 2008-06-30
- 项目状态:已结题
- 来源:
- 关键词:SDS polyacrylamide gel electrophoresisapolipoproteinsbacterial proteinscircular dichroismconformationfluorescence spectrometrygel filtration chromatographyhigh performance liquid chromatographylipid bilayer membranelipid metabolismmolecular pathologyphospholipidsprotein bindingprotein engineeringprotein structurerecombinant proteinstissue /cell culture
项目摘要
DESCRIPTION (provided by applicant): Exchangeable apolipoproteins play a critical role in lipoprotein metabolism. They reversibly associate with lipoprotein surfaces, and are responsible for maintaining lipid homeostasis. Apolipoproteins play an important role in cardiovascular disease but details at the molecular level are still lacking. This project aims to investigate the molecular basis of lipid binding, and gain insight in the lipid-bound conformation of the apolipoprotein. This understanding would benefit the treatment and prevention of cardiovascular disease, in particular arteriosclerosis. The present study proposes to use a well characterized invertebrate apolipoprotein as a model, apolipophorin III (apoLp-III). A combination of structural analysis (circular dichroism and fluorescence spectroscopy) and functional analysis using model phospholipid membranes will be employed. The research plan contains the following aims: (i) investigate helix bundle stability as a function of lipid binding, (ii) identification of lipid factors that trigger apolipoprotein binding, and (iii) obtaining a high resolution structure of the protein in the lipid-bound form. (i) Helix bundle stability may provide a flexible protein facilitating helix bundle opening upon lipid binding. This opening is essential as it exposes the protein's hydrophobic interior to allow direct interaction with lipid. This will be tested by engineering mutant proteins with altered stability properties, and analysis of their lipid binding properties. (ii) Not much is known about the lipid factors that trigger apolipoprotein binding. Model bilayer vesicles composed of a variety of lipids will be used to gain insight in these lipid factors. (iii) The high resolution structure of lipid-free apolipoprotein is known, but still not known for the lipid-bound form. It is crucial to gain insight in this conformation as this is the biologically active form of the protein. We aim to obtain high quality crystals of apoLp-III/phospholipid complexes that diffract at approximately 5 angstrom. This would allow visualization of individual helices, thereby gaining insight in the helix arrangement of the apolipoprotein on the lipid surface.
性状(由申请方提供):可交换载脂蛋白在脂蛋白代谢中起关键作用。它们可逆地与脂蛋白表面结合,并负责维持脂质稳态。载脂蛋白在心血管疾病中起着重要作用,但在分子水平上的细节仍然缺乏。本研究旨在探讨载脂蛋白与脂质结合的分子基础,并深入了解载脂蛋白与脂质结合的构象。这一认识将有利于心血管疾病,特别是动脉硬化的治疗和预防。本研究提出使用一个良好的特点无脊椎动物载脂蛋白作为模型,载脂蛋白III(apoLp-III)。将采用结构分析(圆二色性和荧光光谱)和使用模型磷脂膜的功能分析的组合。研究计划包含以下目标:(i)研究螺旋束稳定性作为脂质结合的函数,(ii)识别触发载脂蛋白结合的脂质因子,以及(iii)获得脂质结合形式的蛋白质的高分辨率结构。(i)受阻束稳定性可提供柔性蛋白质,从而促进脂质结合时螺旋束打开。这个开口是必不可少的,因为它暴露了蛋白质的疏水内部,允许与脂质直接相互作用。这将通过改造具有改变的稳定性特性的突变蛋白质并分析其脂质结合特性来测试。(ii)关于触发载脂蛋白结合的脂质因子知之甚少。模型双层囊泡组成的各种脂质将被用来深入了解这些脂质因素。(iii)无脂质载脂蛋白的高分辨率结构是已知的,但仍不知道的脂质结合形式。了解这种构象是至关重要的,因为这是蛋白质的生物活性形式。我们的目标是获得高质量的apoLp-III/磷脂复合物的晶体,其在约5埃下结晶。这将允许个别螺旋的可视化,从而获得脂质表面上的载脂蛋白的螺旋排列的洞察力。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Role of buried polar residues in helix bundle stability and lipid binding of apolipophorin III: destabilization by threonine 31.
埋藏极性残基在载脂蛋白 III 的螺旋束稳定性和脂质结合中的作用:苏氨酸 31 造成的不稳定。
- DOI:10.1021/bi050502v
- 发表时间:2005
- 期刊:
- 影响因子:0
- 作者:Weers,PaulMM;Abdullahi,WazirE;Cabrera,JamieM;Hsu,Tzu-Chi
- 通讯作者:Hsu,Tzu-Chi
The N-terminus of apolipoprotein A-V adopts a helix bundle molecular architecture.
- DOI:10.1021/bi800515c
- 发表时间:2008-08-19
- 期刊:
- 影响因子:2.9
- 作者:Wong, Kasuen;Beckstead, Jennifer A.;Lee, Dustin;Weers, Paul M. M.;Guigard, Emmanuel;Kay, Cyril M.;Ryan, Robert O.
- 通讯作者:Ryan, Robert O.
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PAUL Michiel WEERS其他文献
PAUL Michiel WEERS的其他文献
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{{ truncateString('PAUL Michiel WEERS', 18)}}的其他基金
Molecular mechanism of apolipoprotein binding to lipopolysaccharides
载脂蛋白与脂多糖结合的分子机制
- 批准号:
7761161 - 财政年份:2010
- 资助金额:
$ 21.38万 - 项目类别:
Mechanism of initiation of lipid binding of apolipoprotein A-I
载脂蛋白 A-I 脂质结合的启动机制
- 批准号:
10189632 - 财政年份:2010
- 资助金额:
$ 21.38万 - 项目类别:
Molecular mechanism of apolipoprotein binding to lipopolysaccharides
载脂蛋白与脂多糖结合的分子机制
- 批准号:
8208976 - 财政年份:2010
- 资助金额:
$ 21.38万 - 项目类别:
Mechanism of initiation of lipid binding of apolipoprotein A-I
载脂蛋白 A-I 脂质结合的启动机制
- 批准号:
10436238 - 财政年份:2010
- 资助金额:
$ 21.38万 - 项目类别:
Molecular mechanism of apolipoprotein binding to lipopolysaccharides
载脂蛋白与脂多糖结合的分子机制
- 批准号:
8005568 - 财政年份:2010
- 资助金额:
$ 21.38万 - 项目类别:
Molecular mechanism of apolipoprotein binding to lipopolysaccharides
载脂蛋白与脂多糖结合的分子机制
- 批准号:
8399726 - 财政年份:2010
- 资助金额:
$ 21.38万 - 项目类别:
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