NADH dehydrogenase (ubiquinone) Fe-S protein 7 (NDUFS7) 是細胞粒線體第一酵素複合體中一個中心次單元蛋白，在物種演化中具有高度保留性。研究指出NDUFS7參與氧化磷酸化(OXPHOS)反應，其功能為該酵素複合體中電子傳遞的最後電子接受者。我們先前的研究發現mitochondrial targeting sequence (MTS)位於NDUFS7的N端，除了MTS我們也發現兩段特別的序列位於NDUFS7的C端，分別為nuclear localization signal (NLS)和nuclear export signal (NES)，這些結果顯示NDUFS7除了被運送進入粒線體之外，還會被運送到細胞核中，但關於調控NDUFS7在不同胞器間的轉移機制依舊是未知的。先前研究指出NDUFS7缺乏與萊氏症候群(Leigh syndrome)或是一些神經疾病是相關的。因此了解NDUFS7在細胞中的分佈機制或是調控功能是一個重要的課題。
近年來研究發現磷酸化修飾(phosphorylation modification)很有可能在調控蛋白分佈及功能上扮演一個重要的角色，而在此篇研究中，主要集中探討磷酸化對於NDUFS7所造成的影響。我們首先在HEK 293細胞中大量表現NDUFS7蛋白，接著以西方點墨的方式分析細胞NDUFS7蛋白上的磷酸化修飾。我們的結果顯示NDUFS7的前驅蛋白所含的酪胺酸會被磷酸化，而透過ATP的刺激可以促使磷酸化的訊號增強。我們也用了軟體預測發現NDUFS7可能是c-Src kinase的受質之一，因此我們在細胞中共同表現NDUFS7和c-Src kinase，結果顯示c-Src kinase可以結合NDUFS7，並且這樣的結合可以增加NDUFS7的磷酸化強度。然而c-Src作用於NDUFS7的磷酸化修飾並不會影響到NDUFS7在細胞中的分布情況或是本身蛋白在第一酵素複合體中的活性。另外我們也確認了NDUFS7第160個位置上的酪胺酸是c-Src kinase主要修飾的位置。此外，我們也發現這個位點的磷酸化修飾對於NDUFS7的蛋白穩定性有顯著影響。接下來的實驗必須進一步探討NDUFS7磷酸化修飾的確切目的，或是其可能調控粒線體的功能。

Human NADH dehydrogenase (ubiquinone) Fe-S protein 7 (NDUFS7), participating in the process of oxidative phosphorylation (OXPHOS), is one of the most conserved core subunits of mitochondrial complex I. In addition to containing a mitochondrial targeting sequence (MTS), a functional nuclear localization signal (NLS) and a nuclear export signal (NES) are both demonstrated to be present in NDUFS7. Deficiency of NDUFS7 is associated with Leigh syndrome (LS) and patients suffering from this disease develop movement disorders and other serious complications. Thus, clearing out the controlling mechanism of NDUFS7 subcellular distribution and its functions at the molecular level is important. Previous studies conducted in our laboratory indicated that NDUFS7 could be located in mitochondria, the cytosol and the nucleus. However, the mechanism of regulating its localization is still unknown. Post–translational modifications are well recognized as the candidates for controlling protein localization and functions. The main purpose of this project is to study the influence of phosphorylation on the subcellular localization of NDUFS7 and/or its involvement in the regulation of NDUFS7 functions. The current results showed that the precursor form of NDUFS7 is phosphorylated at tyrosine residues and enhanced by ATP treatment. In addition, the tyrosine phosphorylation of NDUFS7 could be enhanced by c-Src kinase both in vivo and in vitro. However, the subcellular localization of NDUFS7 is not significantly affected by the expression of c-Src as compared to that of the control groups. Moreover, one of the sites involved in the phosphorylation of NDUFS7 is identified to be tyrosine-160, and the stability of NDUFS7 protein is positively regulated by phosphorylation at this residue. Further studies are on the way to explore the effect of NDUFS7 phosphorylation on mitochondrial functions.

摘要 1
Abstract 3
Abbreviations 6
Introduction 8
1. Mitochondrion, complex I and NDUFS7 8
2. Regulation of protein nucleo-cytoplasmic transport 14
3. Protein Phosphorylation 16
4. Phosphorylation and mitochondria 21
The objective of this study 25
Materials and methods 26
Result 34
1. Evolutionary conservation of iron-sulfur cluster binding domain 34
2. NDUFS7 was tyrosine-phosphorylated in vivo 34
3. The tyrosine phosphorylation of NDUFS7 could be enhanced by ATP treatment 35
4. c-Src interacted with NDUFS7 in vivo 36
5. c-Src phosphorylated NDUFS7 in vivo and in vitro 37
6. The tyrosine-phosphorylated NDUFS7 was mainly present in mitochondria 38
7. Tyrosine-160 was the major site for NDUFS7 phosphorylation by c-Src 39
8. Phosphorylation of NDUFS7 by c-Src did not alter its subcellular localization 40
9. Phosphorylation of NDUFS7 by c-Src did not alter complex I activity 41
10. Tyrosine-160 mutation affected protein stability of NDUFS7 in the presence of c-Src 41
Discussion 43
1. The motif of c-Src phosphorylation and multiple tyrosine phosphorylation sites on NDUFS7? 44
2. Cross-talk between NDUFS7 phosphorylation and SUMOylation 45
3. The biological significance of NDUFS7 phosphorylation 47
Table 50
Figures 51
Reference 66
Appendixes 74

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