NOVEL TARGETS OF THE SULFHYDRYL : CYTOCHROME C OXIDOREDUCTASE ALR

巯基的新靶标：细胞色素 C 氧化还原酶 ALR

• 批准号: 435235019
• 负责人: Professor Dr. Jan Riemer
• 金额: --
• 依托单位: Institut für Biochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/435235019?language=en
• 关键词: NOVEL; TARGETS; SULFHYDRYL; CYTOCHROME; OXIDOREDUCTASE

Disulfide formation in the mitochondrial intermembrane space (IMS) is an essential process that serves in establishing and maintaining protein structures, in regulating protein functions and in driving enzyme reactions as parts of reaction cycles. The mitochondrial disulfide relay, consisting of the two core components ALR/Erv1 and CHCHD4/Mia40, catalyzes disulfide formation in the IMS. CHCHD4 thereby is crucial for IMS import and oxidative folding of many substrates. The major function of ALR was mainly thought to involve regeneration of CHCHD4 to maintain it in its active state. To this end, ALR receives electrons from CHCHD4 and passes them on to cytochrome c in an electron relay reaction. We hypothesize that the role of human ALR expands beyond its originally proposed role as regenerating enzyme for CHCHD4. Instead, we propose that ALR serves as a central electron relay station in the IMS. We recently obtained insights that ALR targets a broad variety of different proteins by identifying interaction partners in proteomic approaches. With this project, we will test whether ALR exerts alternative functions in different tissues, and will therefore identify tissue-specific substrate interactions. We will then characterize the mechanistic, functional and physiological consequences of ALR-dependent oxidation for two novel ALR targets. Moreover, we will investigate the mechanistic differences between substrate handling by CHCHD4 and ALR using a set of different ALR and CHCHD4 targets.Collectively, our work will provide new insights into essential mitochondrial disulfide relay machinery, the biology of the mitochondrial intermembrane space, and into oxidative protein folding in general.

线粒体膜间隙（IMS）中的二硫化物形成是一个重要的过程，用于建立和维持蛋白质结构，调节蛋白质功能和驱动酶反应作为反应循环的一部分。线粒体二硫键中继由两个核心组分ALR/Erv 1和CHCHD 4/Mia 40组成，催化IMS中的二硫键形成。因此，CHCHD 4对于IMS输入和许多底物的氧化折叠至关重要。ALR的主要功能主要被认为涉及CHCHD 4的再生以维持其活性状态。为此，ALR从CHCHD 4接收电子，并在电子中继反应中将它们传递给细胞色素c。我们推测，人ALR的作用扩展到超出其最初提出的作用作为再生酶CHCHD 4。相反，我们建议ALR作为一个中央电子中继站在IMS。我们最近获得的见解，ALR的目标是各种不同的蛋白质，通过确定相互作用的伙伴在蛋白质组学方法。通过这个项目，我们将测试ALR是否在不同组织中发挥替代功能，并因此确定组织特异性底物相互作用。然后，我们将描述两个新的ALR目标的ALR依赖性氧化的机制，功能和生理后果。此外，我们将使用一组不同的ALR和CHCHD 4 targets.Collectively研究CHCHD 4和ALR处理底物之间的机制差异，我们的工作将为基本的线粒体二硫键中继机制，线粒体膜间空间的生物学以及氧化蛋白折叠提供新的见解。