Structural basis of human TRIAP1/PRELI function in mitochondrial lipid transport and apoptosis

线粒体是细胞的能量发生器，因为它们能够将能量转化为可用的形式。它们在协调细胞生长和程序性细胞死亡中也起着重要作用。当这些细胞过程中发生一系列不受欢迎的变化，导致细胞繁殖失控时，癌症等疾病就会出现。在我们确定癌症的病因之前，有必要确切地了解我们的细胞是如何正常工作的。线粒体的功能需要高度协调的蛋白质和脂肪样分子磷脂的供应。在人类中，TRIAP1和PRELI这两个蛋白家族在维持线粒体的脂质平衡中起着关键作用。它们在紧密的复合物中相互作用，促进重要的脂质前体从线粒体外膜转移到线粒体内膜。当细胞处于应激状态时，TRIAP1/PRELI还在防止细胞进入程序性细胞死亡（称为凋亡）中发挥作用。例如，产生大量TRIAP1的乳腺癌女性对化疗反应不佳，因为她们的癌细胞受到保护，不会因药物引起死亡。在本提案中，我们将提出在原子水平上研究TRIAP1/PRELI如何执行这些功能。通过核磁共振（NMR）和x射线衍射方法，将在溶液中成像相关蛋白复合物的形状和柔韧性。从这些结构研究中获得的见解将揭示细胞调节基本方面的机制。反过来，这将使人们更好地了解身体对癌症药物治疗的反应，并可能导致监测当前治疗进展的新治疗方法。

Mitochondria are the power generator for a cell as they are able to convert energy into usable forms. They also play important roles in the orchestrating cell growth and as well as programmed cell death. Diseases such as cancer arise when a series of unwelcome changes occur in some of these cellular processes, causing the cell to multiply out of control. Before we can identify what goes wrong in cancers it is necessary to understand exactly how our cells normally work. Mitochondrial function requires a highly coordinated supply of proteins and fat-like molecules called phospholipids. In humans two families of proteins, called TRIAP1 and PRELI, play a key role in maintaining the lipid balance in mitochondria. They interaction together in a tight complex, which promotes the transfer of important lipid precurcers from the outer mitochondrial membrane to the inner. TRIAP1/PRELI also play a role in preventing cells from entering into programmed cell death (known as apoptosis) when the cell is under stress. For example, women with breast cancer who produce a lot of TRIAP1 respond poorly to chemotherapy by virtue of their cancer cell being protected from the drug-induce death. In this proposal, we will propose to study at the atomic level how TRIAP1/PRELI perform these functions. By using nuclear magnetic resonance (NMR) and X-ray diffraction methods, the shape and flexibility of relevant protein complexes will be imaged in solution. Insight from these structural studies will shed light on the mechanisms that underlie fundamental aspects of cellular regulation. In turn, this would lead to a better understanding of how the body responds to drug treatments in cancer and may lead to new treatments ways of monitoring the progress of current treatments.