Unravelling the molecular network of Lethal (2) giant discs (Lgd) in Drosophila melanogaster.

解开果蝇致命 (2) 巨盘 (Lgd) 的分子网络。

基本信息

批准号：
242945944
负责人：
Professor Dr. Thomas Klein
金额：
--
依托单位：
Institut für Genetik
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/242945944?language=en
关键词：
Unravelling molecular network Lethal giant

项目摘要

The tumoursuppressor Lethal (2) giant discs (Lgd) is a founding member of a protein family that is conserved throughout metazoans. A mutation in one of the human orthologs, LGD2, causes an inherited form of non-syndromic mental retardation. Lgd is involved in the trafficking of transmembrane proteins, such as the Notch receptor, through the endosomal pathway. Our recent work in Drosophila and mammalian cell culture indicates that Lgd is required for the full activity of the ESCRT-III complex through direct interaction with one of its subunits Shrub/Snf7/CHMP4. ESCRT-III is one of five complexes that mediate the pinching off of intraluminal vesicles (ILVs) into the lumen of maturing endosomes. The formation of these ILVs is necessary for the degradation of transmembrane proteins and cancellation of signalling through activated signalling receptors. The exact role of Lgd during this process is not understood. The results of genetic screens performed in our lab suggest that the group of auxiliary ESCRTs, which are required for the full activity of the ESCRT machinery, have a functional relationship with Lgd. Loss of function of the auxiliary ESCRTs in yeast results in the reduction of the activity of the ESCRT-III complex, as has been observed for Lgd. In the frame of this application we will explore the nature of the functional relationship of Lgd to the auxiliary ESCRTs. Moreover, we will complement our performed genetic screens with a molecular one. These experiments will help to understand the function of the evolutionary conserved Lgd protein family.

肿瘤抑制剂致命（2）巨型椎间盘（LGD）是蛋白质家族的创始成员，在整个后生动物中保守。人类直系同源物之一LGD2中的突变引起了一种遗传的非综合性智力迟缓形式。 LGD通过内体途径参与了跨膜蛋白（例如Notch受体）的运输。我们最近在果蝇和哺乳动物细胞培养中的工作表明，通过与其一种亚基灌木/SNF7/CHMP4直接相互作用，LGD是ESCRT-III复合物的全部活性所必需的。 ESCRT-III是介导从腔内囊泡（ILV）夹入成熟内体腔内的五个复合物之一。这些ILV的形成对于跨膜蛋白的降解和通过激活的信号受体取消传导是必要的。 LGD在此过程中的确切作用尚不清楚。在我们的实验室中执行的遗传筛选结果表明，ESCRT机械全部活性所必需的辅助ESCRT与LGD具有功能关系。酵母中辅助ESCRT的功能丧失导致ESCRT-III复合物的活性降低，如LGD所观察到的那样。在此应用程序的框架中，我们将探讨LGD与辅助ESCRT的功能关系的性质。此外，我们将用分子筛选来补充我们所执行的遗传筛选。这些实验将有助于了解进化保守的LGD蛋白家族的功能。