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Mia40 and ALR substrates: initial steps in biogenesis and regulation

Mia40 和 ALR 底物：生物发生和调控的初始步骤

基本信息

批准号：
196651114
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
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/196651114?language=en
关键词：
Mia40 ALR substrates initial steps

项目摘要

The biogenesis and maintenance of mitochondria is fundamental for cellular viability. We characterize the biogenesis and function of mitochondrial intermembrane space (IMS) proteins which are crucial for example for the assembly of the respiratory chain, the induction of apoptosis and the homeostasis of calcium. While some IMS proteins are imported with the help of mitochondrial targeting sequences (MTS), most rely on conserved cysteines and the help of the IMS oxidoreductase Mia40 for import and folding. Mia40 and its sulfhydryl oxidase ALR are part of a recently discovered oxidative machinery that works different than the oxidation machinery in the endoplasmic reticulum. So far the mechanics of this machinery have been mainly elucidated in in vitro experiments and in yeast. However, we lack crucial insights into many fundamental aspects which include the regulation of the machinery, and the associated substrate networks and their regulation in mammalian cells. Moreover, the cytosolic processes prior to import of MTS-less Mia40 substrates remain unclear. This includes for example the identity of recognition signals in the substrates or how the substrates are guided to mitochondria.We recently solved the interactomes of human Mia40 and ALR and thereby revealed that their substrate spectrum is much broader and the structure of many of their substrates more complex than previously anticipated. Likewise, we found that substrates of Mia40 behave very different in the cytosol prior to mitochondrial import compared with MTS-containing substrates. Encouraged by these exciting new data we aim to next identify and characterize cytosolic interaction partners of Mia40 substrates that might be involved in stabilization, proof-reading and targeting of the substrates prior to substrate translocation into the IMS. We also aim to understand further functions associated with Mia40 and ALR by characterizing in mechanistic detail their interplay with selected proteins from their interactomes. Furthermore, we will extend our proteomic analyses to identifying Mia40 and ALR targets during different stress conditions to extend our insights on the dynamics of their interactomes.

线粒体的生物发生和维持是细胞生存的基础。我们描述了线粒体膜间间隙(IMS)蛋白的生物发生和功能，这些蛋白对呼吸链的组装、细胞凋亡的诱导和钙的动态平衡是至关重要的。虽然一些IMS蛋白是在线粒体靶向序列(MTS)的帮助下输入的，但大多数依赖于保守的半胱氨酸和IMS氧化还原酶Mia40的帮助进行输入和折叠。Mia40及其巯基氧化酶ALR是最近发现的氧化机制的一部分，其工作原理与内质网中的氧化机制不同。到目前为止，这种机械的机制主要是在体外实验和酵母中阐明的。然而，我们缺乏对许多基本方面的重要见解，包括机制的调节，以及相关的底物网络及其在哺乳动物细胞中的调节。此外，进口不含MTS的MIA40底物之前的胞浆过程仍不清楚。这包括例如底物中识别信号的一致性或底物如何被引导到线粒体。我们最近解决了人类Mia40和ALR的相互作用，从而揭示了它们的底物光谱比之前预期的要宽得多，许多底物的结构也比之前预期的更复杂。同样，我们发现，与含有MTS的底物相比，Mia40的底物在线粒体导入之前在细胞质中的表现非常不同。受到这些令人兴奋的新数据的鼓舞，我们的目标是下一步确定和表征Mia40底物的胞质相互作用伙伴，这些伙伴可能在底物转移到IMS之前参与底物的稳定、校对和靶向。我们还旨在通过详细描述MIA40和ALR与其相互作用中特定蛋白质的相互作用，来进一步了解它们的相关功能。此外，我们将把我们的蛋白质组学分析扩展到在不同的应激条件下识别Mia40和ALR靶标，以扩展我们对它们相互作用的动力学的洞察。