Functional characterization of the role of evolutionary conserved Rho GTPases at the interface between mitochondria and the endoplasmic reticulum

线粒体和内质网界面上进化保守的 Rho GTP 酶作用的功能表征

• 批准号: 189986593
• 负责人: Professor Dr. Christof Osman
• 金额: --
• 依托单位: Department of Biochemistry and Biophysics
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/189986593?language=en
• 关键词: Functional; characterization; role; evolutionary; conserved

Mitochondria form tight connections with a subfraction of the endoplasmic reticulum (ER). These contact sites are required for Ca2+ and phospholipid exchange between both compartments, which is essential for cell viability. The mechanisms mediating and regulating the interaction between both cellular organelles remain poorly understood. Most recently, a protein complex, named ERMES, has been identified to mediate tethering of mitochondria and the ER in yeast. Mutation of the evolutionary conserved rho GTPase Gem1 results in similar phenotypes compared to ERMES mutants as revealed by a systematic genetic analysis. Moreover, Gem1 and ERMES components physically interact with each other, strongly suggesting a role of Gem1 at mito-ER contact sites. In the proposed study, I will characterize the function of Gem1 at these interfaces and will determine the role of the EF hands and GTPase domains of Gem1 in this process. Mammalian cells lack ERMES counterparts, wherefore I will exploit the mammalian Gem1 homologs, Miro1 and Miro2, as starting points for the investigation of mito-ER contact sites in human cells. Finally, I will perform a systematic large scale analysis to comprehensively define the components impacting on the interaction of mitochondria and the ER. Altogether, these analyses hold the promise to significantly enhance our understanding of the formation and regulation of mito-ER contact sites and their importance for diverse cellular processes.

线粒体与内质网（ER）的一个亚部分形成紧密连接。这些接触位点是两个隔室之间的Ca2+和磷脂交换所必需的，这对细胞活力至关重要。介导和调节两种细胞器之间相互作用的机制仍然知之甚少。最近，一种名为ERMES的蛋白质复合物已被鉴定为介导酵母中线粒体和ER的束缚。系统遗传分析显示，进化保守的rho GTdR Gem1突变导致与ERMES突变体相似的表型。此外，Gem1和ERMES组件物理上相互作用，强烈表明Gem1在mito-ER接触位点的作用。在拟议中的研究中，我将描述的功能，Gem1在这些接口，并将确定的EF手和GTdom域的Gem1在这个过程中的作用。哺乳动物细胞缺乏ERMES对应物，因此我将利用哺乳动物Gem1同源物Miro1和Miro2作为人类细胞中mito-ER接触位点研究的起点。最后，我将进行系统的大规模分析，以全面定义影响线粒体和ER相互作用的组分。总而言之，这些分析有望显着提高我们的理解的形成和调节的mito-ER接触网站和它们的重要性，为不同的细胞过程。