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Probing the roles of membrane and cholesterol on Aβ biogenesis and prion protein interactions

Probing the roles of membrane and cholesterol on Aβ biogenesis and prion protein interactions
探讨膜和胆固醇对 Aβ 生物合成和朊病毒蛋白相互作用的作用
批准号:
10379243
负责人:
JOHN E. STRAUB
金额:
$37.94万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-03-01 至 2024-02-29

项目摘要

项目成果

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中文摘要
翻译
项目摘要 已知序列的蛋白质聚集与多种神经退行性变有关 精神错乱。淀粉样前体蛋白(APP)的家族突变,淀粉样蛋白β源于APP (β)蛋白是一种衍生蛋白,与阿尔茨海默病(AD)的早期发病有关。之后 十五年的基础研究,使用计算机模拟,在实验的指导下 确定决定Aβ体外聚集的因素,该阶段现在开始解决 与AD最相关的问题。它们产生的背景是多么的异质 膜环境、胆固醇和下游与辅因子的相互作用会影响 APP的切割,Aβ的产生,以及Aβ寡聚体和 介导其毒性效应的受体。我们独一无二地准备使用计算模型 回答这些问题,推动AD研究的关键领域取得进展。 在这一计算和理论研究提案中,通过协同实验来增强 研究合作,我们解决基本的生物物理问题 在三个具体目标中阐明了实际影响。(1)发展量化的 了解膜脂组成和结构异质性如何影响 在Genesis Aβ中对APP和对APP处理至关重要的分泌物的划分。(2) 阐明胆固醇在决定淀粉样变性程度中的关键作用 APP差异加工中的裂解。(3)在分子水平上表征 β单体与DNA结合过程中的构象转变和相互作用 寡聚体与细胞内的普鲁恩蛋白(PrPC)有关,与Aβ细胞毒性的可能机制有关。 拟议的协调研究将导致在分子水平上对 对β蛋白的生物发生及其作用至关重要的相互作用网络 AD中的致病因素。通过开发新的计算模型和 确定新的概念,预期的结果可能会改变景观的使用 不仅在AD领域,而且在膜的一般研究中的模拟和理论- 蛋白质的相互作用。!
英文摘要
Project Summary Aggregation of proteins of known sequence is linked to a variety of neurodegenerative disorders. Familial mutations in the Amyloid Precursor Protein (APP), from which the amyloid β (Aβ) protein is derived, have been linked with the early onset of Alzheimer's disease (AD). After fifteen years of fundamental research using computer simulations guided by experiments to identify the factors that determine in vitro aggregation of Aβ, the stage is now set to address questions of utmost relevance to AD. They arise in the context of how heterogeneous membrane environments, cholesterol, and downstream interactions with cofactors affect the cleavage of APP, the production of Aβ, and subsequent interactions of Aβ oligomers and receptors mediating their toxic effects. We are uniquely poised to use computational models to answer these questions and drive advances in critical areas of AD research. In this computational and theoretical research proposal, augmented by synergistic experimental research collaborations, we address fundamental biophysical questions with substantial practical implications articulated in three specific aims. (1) Developing a quantitative understanding of how membrane lipid composition and structural heterogeneity impacts the partitioning of APP and secretases critical to the processing of APP in the genesis Aβ. (2) Elucidating the crucial role cholesterol plays in determining the extent of amyloidogenic cleavage in the differential processing of APP. (3) Characterizing at the molecular-level the conformational transitions and interactions involved in the binding of Aβ monomer and oligomers to cellular prion protein (PrPC), implicated in a plausible mechanism of Aβ cytotoxicity. The proposed coordinated studies will lead to a fundamental molecular-level understanding of the network of interactions that are essential to the biogenesis of Aβ protein and its role as a pathogenic agent in AD. Through the development of novel computational models and identification of new concepts, the expected outcomes could change the landscape for the use of simulations and theory not only in the AD field but also in the general study of membrane- protein interactions.!
期刊论文(29)
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会议论文
Structure of APP-C991-99 and implications for role of extra-membrane domains in function and oligomerization.
APP-C991-99 的结构以及膜外结构域在功能和寡聚化中的作用的影响。
DOI: 10.1016/j.bbamem.2018.04.002
发表时间: 2018
期刊: Biochimica et biophysica acta. Biomembranes
影响因子: --
作者: [Pantelopulos,GeorgeA, Straub,JohnE, Thirumalai,D, Sugita,Yuji]
通讯作者: Sugita,Yuji
Molecular Insights into Human Hereditary Apolipoprotein A-I Amyloidosis Caused by the Glu34Lys Mutation.
Glu34Lys 突变引起的人类遗传性载脂蛋白 A-I 淀粉样变性的分子见解。
DOI: 10.1021/acs.biochem.8b00817
发表时间: 2018
期刊: Biochemistry
影响因子: 2.9
作者: [Morgado,Isabel, Panahi,Afra, Burwash,AndrewG, Das,Madhurima, Straub,JohnE, Gursky,Olga]
通讯作者: Gursky,Olga
DOI: 10.1002/prot.24934
发表时间: 2015-12
期刊: Proteins
影响因子: 2.9
作者: [Viswanath S, Dominguez L, Foster LS, Straub JE, Elber R]
通讯作者: Elber R
Characterizing the transmembrane domains of ADAM10 and BACE1 and the impact of membrane composition.
表征 ADAM10 和 BACE1 的跨膜结构域以及膜组成的影响。
DOI: 10.1016/j.bpj.2023.08.025
发表时间: 2023
期刊: Biophysical journal
影响因子: 3.4
作者: [Abraham,ConorB, Xu,Lin, Pantelopulos,GeorgeA, Straub,JohnE]
通讯作者: Straub,JohnE
15
    Probing the role of membrane and cholesterol on APP-C99 structure and dynamics
    Probing the roles of membrane and cholesterol on Aβ biogenesis and prion protein interactions
    Probling the Principles of Amyloid Formation
    Probing the Principles Governing Protein Aggregation
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