Molecular mechanisms of signal transduction by the mitochondrial life-span regulators p66Shc and Sirtuins

线粒体寿命调节因子 p66Shc 和 Sirtuins 信号转导的分子机制

• 批准号: 106962688
• 负责人: Professor Dr. Clemens Steegborn
• 金额: --
• 依托单位: Arbeitsgruppe Biomolekulare Massenspektrometrie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/106962688?language=en
• 关键词: Molecular; mechanisms; signal; transduction; mitochondrial

Several proteins have been identified which are involved in cellular aging processes and related diseases, including Sirtuin proteins and p66Shc. They are part of a complex signaling network synchronizing processes such as metabolic adaptation and apoptosis.Mammals have several isoforms of the NAD+-dependent protein deacetylases of the Sirtuin family. Three mitochondrial isoenzymes appear to contribute to regulation of energy metabolism and stress response. Similarly, the mitochondrial Shc isoform p66Shc acts as stress sensor and apoptosis regulator. Most molecular details of these signaling systems and their connections remain to be identified and might reveal attractive intervention points for therapy of aging-related diseases. We aim to identify and study in molecular detail the protein/protein interactions of the mitochondrial signaling proteins p66Shc, Sirt3, and Sirt5, which contribute to their localization, regulation, and substrate recognition. Interactions will be detected through affinity experiments, and substrates and regulators characterized in activity assays. Crystal structures of complexes with peptides, proteins, and small molecules will be solved. The interactions will be analyzed by site-directed mutagenesis, and we will attempt to exploit this information for the development of specific modulators.

已经鉴定了几种参与细胞衰老过程和相关疾病的蛋白质，包括Sirtuin蛋白和p66 Shc。它们是一个复杂的信号网络的一部分，同步过程，如代谢适应和细胞凋亡。哺乳动物有几个异构体的NAD+依赖性蛋白质去乙酰化酶的Sirtuin家族。三种线粒体同工酶似乎有助于调节能量代谢和应激反应。类似地，线粒体Shc同种型p66 Shc充当应激传感器和凋亡调节剂。这些信号系统及其连接的大多数分子细节仍有待确定，并可能揭示有吸引力的干预点，治疗衰老相关疾病。我们的目标是确定和研究的线粒体信号蛋白p66 Shc，Sirt 3和Sirt 5，这有助于他们的本地化，调节和底物识别的蛋白质/蛋白质相互作用的分子细节。将通过亲和力实验检测相互作用，并在活性测定中表征底物和调节剂。与肽，蛋白质和小分子的复合物的晶体结构将被解决。将通过定点诱变分析相互作用，我们将尝试利用这些信息开发特定的调制器。