Conformational and functional analysis of Apolipoprotein E
载脂蛋白E的构象和功能分析
基本信息
- 批准号:10557079
- 负责人:
- 金额:$ 44.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-05-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AdoptedAffinityAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease riskApolipoprotein EBindingBinding ProteinsBiochemicalCardiovascular PathologyCardiovascular systemCarrier ProteinsCerebrospinal FluidCholesterol HomeostasisComplexDataDiseaseEquilibriumExhibitsFluorescence Resonance Energy TransferFluorescence SpectroscopyHealthHeterogeneityLate Onset Alzheimer DiseaseLengthLigandsLinkLipid BindingLipidsLipoproteinsMethodsModelingMolecularMolecular ConformationMovementPathogenicityPhysiologicalPlasmaPlayPoint MutationPropertyProtein ConformationProtein FragmentProtein IsoformsProteinsRiskRoleStructural ModelsStructureTestingThinkingTimeToxic effectVariantVesicleapolipoprotein E-3cardiovascular disorder riskconformerexperimental studyflexibilitygenetic risk factorinterestlipid transportmonomernanodisknanosecondnovelnovel strategiesnovel therapeutic interventionparticleprotein functionprotein oligomerrecruitsingle moleculesingle-molecule FRETsmall moleculestructural biology
项目摘要
ABSTRACT
The ε4-allele isoform of apolipoprotein E (ApoE4) plays a key-role in Alzheimer's disease and
cardiovascular pathologies. A large body of evidence support that conformations of the protein are instrumental
in its contribution to function and disease; yet, much remains unknown about the conformational ensemble of
full-length ApoE and its role in protein (dis)function, largely because of its elevated propensity for
aggregation/oligomerization and inherent flexibility.
In our lab, we have overcome these complications by harnessing state-of-the-art single-molecule
fluorescence spectroscopy and, for the first time, we are able to access the structural ensemble of the
monomeric full-length ApoE4 (free in solution, embedded in oligomers, and bound to lipids). Our preliminary
data clearly indicate that ApoE4 adopts at least three distinct conformers – previously unidentified – that
coexist in equilibrium. These conformers are highly dynamic and malleable to oligomerization and lipid binding.
These novel observations led us to hypothesize that single-point mutations and small molecules can
perturb the structural ensemble favoring/disfavoring specific “pathogenic” conformations, whereas interaction
with ligands (e.g. lipids) alters the equilibrium between the different conformers selecting for specific
conformations that are required for protein function. Our approach will allow us to determine the conformational
properties of ApoE, probe current structural models, and test our hypothesis. The specific aims are as follows:
1) determine the conformational changes and domain movements within the pathogenic ApoE4 and elucidate
how point mutations and small molecules modulate protein toxicity; 2) understand the mechanism of lipid
interactions, from synthetic lipid vesicles to physiological lipoproteins.
A comprehensive description of the structural conformations and dynamics of ApoE in the presence
and absence of lipids will shed light on the molecular mechanism behind its role in health and disease, paving
the way to developing new therapeutic strategies.
摘要
载脂蛋白E(ApoE 4)的ε4等位基因亚型在阿尔茨海默病中起关键作用,
心血管疾病大量的证据支持蛋白质的构象是工具性的
在其功能和疾病的贡献;然而,许多仍然未知的构象合奏
全长ApoE及其在蛋白质(功能障碍)中的作用,主要是因为其增加的倾向性,
聚合/低聚和固有的灵活性。
在我们的实验室里,我们通过利用最先进的单分子技术
荧光光谱,并为第一次,我们能够访问的结构合奏的
单体全长ApoE 4(游离于溶液中,包埋在寡聚体中,并与脂质结合)。我们的初步
数据清楚地表明,ApoE 4采用了至少三种不同的构象-以前未鉴定-,
平衡共存。这些构象异构体是高度动态的,并且对于寡聚化和脂质结合具有延展性。
这些新的观察使我们假设单点突变和小分子可以
干扰有利于/不利于特定的“致病”构象的结构系综,而相互作用
与配体(如脂质)的结合改变了不同构象之间的平衡,
蛋白质功能所需的构象。我们的方法将使我们能够确定构象
ApoE的特性,探测当前的结构模型,并验证我们的假设。具体目标如下:
1)确定致病性ApoE 4内的构象变化和结构域运动,并阐明
点突变和小分子如何调节蛋白质毒性; 2)了解脂质代谢的机制
从合成脂质囊泡到生理脂蛋白的相互作用。
ApoE的结构构象和动力学的全面描述,
和缺乏脂质将揭示其在健康和疾病中作用背后的分子机制,
开发新的治疗策略的方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Andrea Soranno其他文献
Andrea Soranno的其他文献
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{{ truncateString('Andrea Soranno', 18)}}的其他基金
A multipronged investigation of SARS-CoV-2 genome packaging
SARS-CoV-2 基因组包装的多管齐下研究
- 批准号:
10444410 - 财政年份:2022
- 资助金额:
$ 44.45万 - 项目类别:
A multipronged investigation of SARS-CoV-2 genome packaging
SARS-CoV-2 基因组包装的多管齐下研究
- 批准号:
10610414 - 财政年份:2022
- 资助金额:
$ 44.45万 - 项目类别:
Combined single-molecule fluorescence confocal and dual-trap optical tweezers
组合单分子荧光共焦和双阱光镊
- 批准号:
10177519 - 财政年份:2021
- 资助金额:
$ 44.45万 - 项目类别:
ApoE isoform-specific structure: Insights on biology and pathobiology
ApoE 亚型特异性结构:生物学和病理学的见解
- 批准号:
10407943 - 财政年份:2021
- 资助金额:
$ 44.45万 - 项目类别:
ApoE isoform-specific structure: Insights on biology and pathobiology
ApoE 亚型特异性结构:生物学和病理学的见解
- 批准号:
10667462 - 财政年份:2021
- 资助金额:
$ 44.45万 - 项目类别:
Conformational and functional analysis of Apolipoprotein E
载脂蛋白E的构象和功能分析
- 批准号:
10334412 - 财政年份:2019
- 资助金额:
$ 44.45万 - 项目类别:
Conformational and functional analysis of Apolipoprotein E
载脂蛋白E的构象和功能分析
- 批准号:
10088363 - 财政年份:2019
- 资助金额:
$ 44.45万 - 项目类别:
Conformational and functional analysis of Apolipoprotein E
载脂蛋白E的构象和功能分析
- 批准号:
9922840 - 财政年份:2019
- 资助金额:
$ 44.45万 - 项目类别:
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