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

 描述(申请人提供)：已知序列的蛋白质聚集与多种神经退行性疾病有关。与阿尔茨海默病(AD)相关的淀粉样前体蛋白(APP)的家族突变与淀粉样病的早期发病有关。在这项计算和理论研究提案中，通过协同实验研究合作，我们将确定膜环境中APP的99个氨基酸跨膜片段(APP-C99)的结构和动力学，以解决在三个特定目标中阐明的基本生物物理问题。(1)我们将探索长度、序列和膜组成对APP-C99单体结构的影响。(2)膜组成和C99序列对APP-C99二聚体的结构和缔合稳定性以及单体-二聚体的平衡也有影响。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类似物相互作用，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单体和二聚体以及胆固醇相互作用网络的基本分子水平的了解，这些被认为是我们理解APP-C99处理、A？聚集途径以及潜在的基于知识的AD治疗设计的基本组成部分。

 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.