Understanding the structural basis of specificity in mitochondrial lipid transport and its role in drug resistance

线粒体是细胞的发电机，在细胞生长和程序性细胞死亡中起重要作用。当这些细胞过程中发生一系列不受欢迎的变化时，就会出现癌症等疾病。线粒体的健康需要高度协调的蛋白质和脂肪样分子的供应，这些分子被称为磷脂，形成一个包围蛋白质机器的膜。PRELI/Ups蛋白质家族是维持正确磷脂平衡的基础。在这项提案中，我们计划可视化的机制，通过这种机制，特定的线粒体磷脂可以区分和分布在不同的膜之间。通过先进的结构测定方法，如X射线晶体学和核磁共振（NMR），生物分子的形状，灵活性和相互作用将在溶液中成像。从这些结构研究的见解将结合细胞的方法来了解控制脂质转运的PRELI/UPS系统的功能。这将为线粒体调控的基本机制以及可能导致疾病的异常途径提供新的线索。反过来，这将导致更好地了解身体如何对癌症药物治疗以及新治疗做出反应，并监测其可能的有效性。

Mitochondria are the power generators for a cell and play important roles in cell growth and as well as programmed cell death. Diseases such as cancer arise when a series of unwelcome changes occur in these cellular processes. Mitochondrial health requires a highly coordinated supply of proteins and fat-like molecules known as phospholipids that form a membrane that encloses the protein machinery. The PRELI/Ups family of proteins is fundamental to maintaining the correct phospholipid balance. In this proposal we plan to visualise the mechanisms by which specific mitochondrial phospholipids can be discriminated and distributed between distinct membranes. By advanced structure determination methods, such as X-ray crystallography and nuclear magnetic resonance (NMR), the shape, flexibility and interaction of biological molecules will be imaged in solution. Insight from these structural studies will be combined with cellular approaches to understand the features that control lipid transport by the PRELI/Ups system. This will shed new light on the mechanisms that underlie fundamental aspects of mitochondrial regulation, and the aberrant pathways that can lead to disease. In turn, this would lead to a better understanding of how the body responds to drug treatments in cancer as well as new treatments and monitoring their likely effectiveness.