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

了解线粒体脂质转运特异性的结构基础及其在耐药性中的作用

• 批准号: MR/S021191/1
• 负责人: Steve Matthews
• 金额: $ 68.36万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS021191%2F1
• 关键词: Understanding; structural; basis; specificity; mitochondrial

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.

线粒体是细胞的发电机，并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，就会产生诸如癌症之类的疾病。线粒体健康需要高度协调的蛋白质和类似脂肪的分子，称为磷脂，形成包围蛋白质机械的膜。蛋白质的序列/UPS家族对于维持正确的磷脂平衡至关重要。在此提案中，我们计划可视化可以区分特定线粒体磷脂的机制，并在不同的膜之间进行区分和分布。通过先进的结构测定方法，例如X射线晶体学和核磁共振（NMR），将在溶液中成像生物分子的形状，柔韧性和相互作用。这些结构研究的洞察力将与细胞方法相结合，以了解控制脂质/UPS系统的脂质转运的特征。这将为线粒体调节的基本方面以及可能导致疾病的异常途径的基本机制提供新的启示。反过来，这将使人们更好地了解身体对癌症药物治疗以及新疗法的反应并监测其可能有效性。

项目成果

An intermolecular hydrogen bonded network in the PRELID-TRIAP protein family plays a role in lipid sensing.

• DOI: 10.1016/j.bbapap.2022.140867
• 发表时间: 2022-10
• 期刊: Biochimica et biophysica acta. Proteins and proteomics
• 作者: X. Miliara;T. Tatsuta;Akinori Eiyama;T. Langer;S. Rouse;Steve Matthews

Structural determinants of lipid specificity within Ups/PRELI lipid transfer proteins

• DOI: 10.1038/s41467-019-09089-x
• 发表时间: 2019-03-08
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Miliara, Xeni;Tatsuta, Takashi;Langer, Thomas
• 通讯作者: Langer, Thomas