Project 1 - Structural basis of HDL assembly
项目1 - HDL组装的结构基础
基本信息
- 批准号:9073920
- 负责人:
- 金额:$ 22.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-15 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:ATP binding cassette transporter 1Anti-Inflammatory AgentsAnti-inflammatoryApolipoprotein A-IApolipoprotein A-IIApolipoproteinsAtherosclerosisBiological AssayBiological ProcessBiologyBlood VesselsCationsCellsChemicalsChemistryCholesterolComplexComputer SimulationComputersComputing MethodologiesConsensusCoronary ArteriosclerosisEnvironmentEvolutionExtracellular DomainFutureGeneticHeart DiseasesHigh Density Lipoprotein CholesterolHigh Density LipoproteinsHomology ModelingLearningLipidsLipoproteinsLiquid substanceLow-Density LipoproteinsMammalian CellMass Spectrum AnalysisMembraneMetabolic PathwayModelingMolecularMolecular ConformationMolecular ModelsMutagenesisMutationMyocardial InfarctionNucleosome Core ParticleOsteichthyesPharmaceutical PreparationsPhosphatidylcholine-Sterol O-AcyltransferasePhospholipidsProgram Research Project GrantsProteinsPumpResolutionRiskRoleShapesSite-Directed MutagenesisStructureSulfhydryl CompoundsTestingThree-Dimensional ImageTimeTubeTweensatherogenesisbasecardiovascular risk factorcrosslinkdensitydrug developmentextracellularinnovationinterdisciplinary approachmolecular modelingmonolayermonomermultidisciplinarynanoscalenovelparticlepreventprogramsreconstitutionscaffoldsimulationsoundtomography
项目摘要
We hypothesize that apoA-I is the major HDL platform and functions as a conformationally dynamic scaffold
that facilitates the interaction of a host of other apolipoproteins and lipid remodeling factors. It follows from this
hypothesis that a detailed understanding of HDL assembly is not possible through traditional unidisciplinary
approaches but requires an integrated multidisciplinary team approach. Our objective in this project is to use
that approach to understand, in unprecedented detail, the structural basis for HDL assembly. We will combine in
silico approaches with more traditional in-solution experimental approaches: i) high resolution mass
spectrometry combined with thiol-cleavable cross-linking chemistry (Core D), ii) site-directed mutagenesis (Core
D), and iii) functional studies (Core C). To achieve this objective, we propose three specific aims: Aim 1: Three
early steps in HDL assembly: i) ApoA-I monomer structure and dynamics. We will experimentally test our
models using cross-linking and site-directed mutagenesis (Core D) and assays of function (Core C). ii) ABCA1
structure and dynamics. We will use computational methods to develop the extracellular- and intracellular-facing
conformations and the molecular basis for this conformational cycle of ABCA1 and how this cycle produces a
phospholipid pump (Core B). Using purified and mammalian cell-derived ABCA1, we will experimentally test the
models by, respectively, mass spectroscopy-chemical cross-linking (Cores C and D) and site-directed
mutagenesis (Core D) using cell-based assays of HDL function and quantification of HDL particles (Core C). iii)
Physical basis for assembly of nascent HDL. We will test the monolayer pleating hypothesis by MD simulations,
examining, for example, the effects of lysoPC and FFA on disc-membrane fission and mechanisms of lipidation
of dimeric apoA-I (Core B). Mutagenesis will target key Lys residues in the extracellular domain of ABCA1
where pleating and apoA-I association is propose to occur. High resolution EM tomography will be used to
examine 3D images of budding discs under various conditions of lipid composition. Aim 2: Two middle steps in
HDL assembly: i) Simulations of the interactions of LCAT with apoA-I and dHDL (Core B). The models will be
experimentally tested using cross-linking and mutagenesis (Heinecke). ii) Simulations of the interactions of
apoA-II with apoA-I and HDL. The models will be experimentally tested using cross-linking (Davidson). Aim 3:
Three later steps in HDL assembly. i) ABCG1 structure and dynamics. The models will be developed using
homology modeling with MODELLER, double state normal mode analysis and MD simulations (Core B). ii)
Detailed molecular models of PLTP and its interactions with HDL (Davidson). The models will be
experimentally tested using homology modeling with MODELLER (Core B), assays of function (Core C), cross-
linking (Cores C and D) and high resolution EM tomography. iii) Detailed molecular models of the interactions of
PON-1 with HDL. ApoA-I mutations in helical repeat 4 in apoA-I (or other domains identified by Davidson) will
be reconstituted as dHDL and PON-1 activity determined.
我们假设apoA-I是主要的HDL平台,并作为构象动态支架起作用
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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Jere P Segrest其他文献
515 THE INHERITANCE OF HDL2 CHOLESTEROL AND ITS POSSIBLE ROLE IN CORONARY HEART DISEASE
515 HDL2 胆固醇的遗传及其在冠心病中可能的作用
- DOI:
10.1203/00006450-198504000-00545 - 发表时间:
1985-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Joann N Bodurtha;Richard M Schieken;Lindon J Eaves;Walter E Nance;Jere P Segrest - 通讯作者:
Jere P Segrest
Jere P Segrest的其他文献
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{{ truncateString('Jere P Segrest', 18)}}的其他基金
Mechanisms of phospholipid/cholesterol translocation by ABCA1
ABCA1 的磷脂/胆固醇易位机制
- 批准号:
10711264 - 财政年份:2016
- 资助金额:
$ 22.03万 - 项目类别:
Multidisciplinary Approaches to HDL Structure, Assembly and Function
HDL 结构、组装和功能的多学科方法
- 批准号:
9073915 - 财政年份:2016
- 资助金额:
$ 22.03万 - 项目类别:
Computational and Experimental Studies of Structure/ Dynamics of HDL Assemblies
HDL 组件结构/动力学的计算和实验研究
- 批准号:
8242746 - 财政年份:2011
- 资助金额:
$ 22.03万 - 项目类别:
Dynamics of LCAT activation and lipoprotein remodeling
LCAT 激活和脂蛋白重塑的动力学
- 批准号:
8038974 - 财政年份:2010
- 资助金额:
$ 22.03万 - 项目类别:
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