The Structure and Assembly of Peptide Aggregates

描述（由申请人提供）：蛋白质和肽的聚集是许多疾病的原因，包括阿尔茨海默病和帕金森病。了解肽聚集机制的细节是在分子水平上理解这些疾病的先决条件。本计画将结合生物物理学技术来描述一种朊病毒肽与人类γ-D-晶体蛋白的结构与组装机制，重点有三个具体目标：（1）结合同位素编辑红外光谱、差示扫描量热法、肽设计与修饰，剖析朊病毒肽在溶液中形成β-折叠的机制;（2）通过红外、电子显微镜和原子力显微镜的组合探索朊病毒肽纤维的形态、链排列和形成动力学;（3）将同位素编辑的红外技术应用于γ-D-晶状体蛋白中蛋白质聚集的研究。这些研究将导致在一个全面的描述的聚集过程中，从最初的构象变化的个别多肽的肽聚集的早期阶段，形成大的纤维状沉淀物。这种对聚集过程的彻底描述将为在分子水平上更好地理解许多疾病奠定基础，并为开发新的药物策略开辟道路。

DESCRIPTION (provided by applicant): The aggregation of proteins and peptides is responsible for a number of diseases, including AIzheimer's and Parkinson's diseases. An understanding of the details of peptide aggregation mechanisms is prerequisite to understanding these diseases on the molecular level. This project will use a combination of biophysical techniques to describe the structure and assembly mechanism of a prion peptide and human gamma-D-crystallin, focusing on three specific aims: (1) dissecting the mechanism of beta-sheet formation by prion peptides in solution, using a combination of isotope-edited infrared (IR) spectroscopy, differential scanning calorimetry, and peptide design and modification; (2) exploring the morphology, strand alignment, and formation kinetics of prion peptide fiber through a combination of IR, electron microscopy, and atomic force microscopy; and (3) applying the isotope-edited IR technique to the study of protein aggregation in gamma-D-crystallin proteins. These studies will result in a comprehensive description of the aggregation process, from the initial conformational changes of individual polypeptides to the early stages of peptide aggregation to the formation of large fibrous precipitates. Such a thorough description of the aggregation process will lay a foundation for an improved understanding of many diseases at the molecular level, and also open the way for the development of new pharmaceutical strategies.