人热休克因子hHSF1与hHSF2的三维结构及其功能关系研究

项目名称： 人热休克因子hHSF1与hHSF2的三维结构及其功能关系研究

项目编号： No.31270788

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 刘威

作者单位： 中国人民解放军第三军医大学

项目金额： 80万元

中文摘要： 热休克转录因子（HSF）是调控细胞应激反应、发育与分化、细胞代谢与衰老等重要生理活动的核心因子，同时又与多种癌症及早老型痴呆症、帕金森综合症等神经退休性疾病的发生密切相关。真核细胞HSF的激活是一个多层次调控的复杂过程，其中许多细节与分子机制目前仍不清楚。当前的研究热点包括：1，HSF的上游调控因子与作用机理；2，HSF被激活形成三体的结构基础与相关分子机制；3，决定HSF下游调控对象特异性的结构元件。这些问题的阐明都依赖于HSF分子三维结构的解析。本课题的目标是通过解析此家族两个重要成员HSF1与HSF2的全长晶体结构，以及DNA结合结构域与各自底物DNA的复合物结构，在结构分析的基础上，结合其他实验技术，深入探讨结构与功能关系，揭示HSF活化过程中若干重要分子事件发生的结构基础，阐释可能分子机制。研究结果不仅将为HSF的基础研究领域带来突破性进展，还可为多种疾病相关医学研究提供新思路。

中文关键词： 热休克因子；DNA结合结构域；高分辨率结构；分子动力学模拟；翻译后修饰

英文摘要： The heat shock response (HSR) is an ordered genetic response to diverse environmental and physiological stressors that results in the immediate induction of genes encoding molecular chaperones, proteases, and other proteins essential for protection and recovery from cellular damage associated with the increase of misfolded, unfolded and aggregated proteins. The list of "stressors" that activate transcription of these heat shock genes is large and includes various acute and chronic conditions such as elevated temperatures, heavy metals, small molecule chemical toxicants, infection, and oxidative stress. Mutations and environmental influences including inflammation, ischemia, tissue wounding and repair, cancer, and neurodegenerative diseases are also associated with the aberrant expression of heat shock proteins. In eukaryotes, HSR is mediated by a positive control upon the hsp genes from specific activator proteins, called heat shock transcription factors, HSFs. Mammals express four members of the HSF familiy, HSF 1-4, which share well-conserved DNA-binding and trimerization domains. Our aim in this project is to explore the molecular basis of mechanisms that control HSF activity and protein homeostasis networks in cells from the perspective of structural biology. Our proposal encompasses the determination of the

英文关键词： heat shock factor；DNA-binding domain；high-resolution structures；molecular dynamics simulation；post-translational modification