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

线粒体是细胞的发电机，因为它们能够将能量转化为可用的形式。它们还在协调细胞生长和程序性细胞死亡中发挥重要作用。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，导致细胞失控地繁殖。在我们确定癌症中的问题之前，有必要确切地了解我们的细胞通常是如何工作的。线粒体功能需要高度协调的蛋白质和脂肪样分子（称为磷脂）的供应。在人类中，称为TRIAP 1和PRELI的两个蛋白质家族在维持线粒体中的脂质平衡方面发挥关键作用。它们在紧密的复合物中相互作用，促进重要的脂质代谢物从线粒体外膜转移到线粒体内膜。TRIAP 1/PRELI还在细胞处于应激状态时防止细胞进入程序性细胞死亡（称为凋亡）中发挥作用。例如，患有乳腺癌的女性产生大量的TRIAP 1，由于其癌细胞被保护免受药物诱导的死亡，因此对化疗的反应很差。在本提案中，我们将提议在原子水平上研究TRIAP 1/PRELI如何执行这些功能。通过使用核磁共振（NMR）和X射线衍射方法，将在溶液中对相关蛋白质复合物的形状和柔性进行成像。从这些结构研究的见解将阐明细胞调节的基本方面的机制。反过来，这将导致更好地了解身体对癌症药物治疗的反应，并可能导致新的治疗方法来监测当前治疗的进展。

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.