Probing the role of membrane and cholesterol on APP-C99 structure and dynamics

探讨膜和胆固醇对 APP-C99 结构和动力学的作用

• 批准号: 8887509
• 负责人: JOHN E. STRAUB
• 金额: $ 31.19万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887509
• 关键词: Accounting; Address; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid Protein AA; Amyloid beta-Protein Precursor; Amyloidosis; Binding; Binding Sites; C-terminal; Cause of Death; Cholesterol; Collaborations; Computer Simulation; Computing Methodologies; Consensus; Dependence; Development; Dimerization; Disease; Elderly; Environment; Environmental Risk Factor; Equilibrium; Future; Goals; Integral Membrane Protein; Knowledge; Lead; Left; Length; Link; Membrane; Membrane Proteins; Modeling; Molecular; Mutation; Nature; Neurodegenerative Disorders; Peptides; Physiological; Play; Population; Preventive; Process; Production; Property; Proteins; Research; Research Proposals; Role; Senile dementia; Staging; Structure; System; Theoretical model; Therapeutic; aggregation pathway; amyloid precursor protein processing; base; cholesterol analog; computer studies; design; dimer; early onset; familial Alzheimer disease; infancy; insight; knowledge base; monomer; novel; peptide A; protein aggregation; public health relevance; research study; secretase

 DESCRIPTION (provided by applicant): 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 ß (Aß) protein associated with Alzheimer's Disease (AD) is derived, have been linked with the early onset of amyloid disease. In this computational and theoretical research proposal, augmented by synergistic experimental research collaborations, we will determine the structure and dynamics of the 99 amino acid transmembrane fragment of APP (APP-C99) in membrane environments in order to address fundamental biophysical questions articulated in three Specific Aims. (1) We will explore how length, sequence, and membrane composition influence the structure of the APP-C99 monomer. (2) The structures of APP-C99 dimers and the associated stability as well as the monomer-dimer equilibrium are also influenced by membrane composition and C99 sequence. We will investigate the influence of these environmental factors on the structure and dynamics of dimer formation. (3) We will also determine how APP-C99 interacts with cholesterol and cholesterol-analogs, as well as how those interactions influence APP-C99 structure and dimerization. The proposed coordinated studies will lead to a fundamental molecular-level understanding of the network of interactions of APP-C99 monomer and dimer, and cholesterol, which are recognized to be essential components of our understanding of APP-C99 processing, the Aß aggregation pathway, and potentially in the design of knowledge-based therapy for AD.

 描述（由适用提供）：已知序列的蛋白质的聚集与多种神经退行性疾病有关。淀粉样蛋白前体蛋白（APP）中的家族突变，淀粉样β（Aß）蛋白与阿尔茨海默氏病相关（AD）与淀粉样蛋白疾病的早期发作有关。在这项计算和理论研究建议中，由协同实验研究合作增强，我们将确定膜环境中APP（APP-C99）99氨基酸跨膜片段的结构和动态，以解决三个特定目标中阐明的基本生物物理问题。 （1）我们将探讨长度，序列和膜组成如何影响APP-C99单体的结构。 （2）APP-C99二聚体的结构以及相关的稳定性以及月二聚体平衡也受膜组成和C99序列的影响。我们将研究这些环境因素对二聚体形成的结构和动力学的影响。 （3）我们还将确定APP-C99如何与胆固醇和胆固醇 - 纳alogs相互作用，以及这些相互作用如何影响App-C99的结构和二聚化。拟议的协调研究将导致对App-C99单体和二聚体相互作用网络和胆固醇的相互作用网络的基本理解，而胆固醇被认为是我们对App-C99处理，Aß聚集途径的理解的重要组成部分，以及在基于知识的AD的设计中潜在的APP-C99处理。