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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 詹迺立(Nei-Li Chan) | |
| dc.contributor.author | Sheng Ou Yang | en |
| dc.contributor.author | 歐陽陞 | zh_TW |
| dc.date.accessioned | 2021-06-15T13:29:50Z | - |
| dc.date.available | 2016-02-24 | |
| dc.date.copyright | 2016-02-24 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-02-04 | |
| dc.identifier.citation | 參考文獻
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Kahana, C. (2007). Ubiquitin dependent and independent protein degradation in the regulation of cellular polyamines. Amino Acids 33(2): 225-230. 34. Wu, H. Y., et al. (2015). Structural basis of antizyme-mediated regulation of polyamine homeostasis. Proc Natl Acad Sci U S A 112(36): 11229-11234. 35. Heller, J. S., et al. (1976). Induction of a protein inhibitor to ornithine decarboxylase by the end products of its reaction. Proc Natl Acad Sci U S A 73(6): 1858-1862. 36. Kahana, C. (2009). Antizyme and antizyme inhibitor, a regulatory tango. Cell Mol Life Sci 66(15): 2479-2488. 37. Iwata, S., et al. (1999). Anti-tumor activity of antizyme which targets the ornithine decarboxylase (ODC) required for cell growth and transformation. Oncogene 18(1): 165-172. 38. Koike, C., et al. (1999). Sensitivity to polyamine-induced growth arrest correlates with antizyme induction in prostate carcinoma cells. Cancer Res 59(24): 6109-6112. 39. Coffino, P. (2001). Antizyme, a mediator of ubiquitin-independent proteasomal degradation. Biochimie 83(3-4): 319-323. 40. Matsufuji, S., et al. (1995). Autoregulatory frameshifting in decoding mammalian ornithine decarboxylase antizyme. Cell 80(1): 51-60. 41. Rom, E. and C. Kahana (1994). Polyamines regulate the expression of ornithine decarboxylase antizyme in vitro by inducing ribosomal frame-shifting. Proc Natl Acad Sci U S A 91(9): 3959-3963. 42. Kurian, L., et al. (2011). Polyamine sensing by nascent ornithine decarboxylase antizyme stimulates decoding of its mRNA. Nature 477(7365): 490-494. 43. Nilsson, J., et al. (1997). Polyamines regulate both transcription and translation of the gene encoding ornithine decarboxylase antizyme in mouse. Eur J Biochem 250(2): 223-231. 44. Palanimurugan, R., et al. (2004). Polyamines regulate their synthesis by inducing expression and blocking degradation of ODC antizyme. EMBO J 23(24): 4857-4867. 45. Kitani, T. and H. Fujisawa (1984). Purification and some properties of a protein inhibitor (antizyme) of ornithine decarboxylase from rat liver. J Biol Chem 259(16): 10036-10040. 46. Cohavi, O., et al. (2009). Docking of antizyme to ornithine decarboxylase and antizyme inhibitor using experimental mutant and double-mutant cycle data. J Mol Biol 390(3): 503-515. 47. Hoffman, D. W., et al. (2005). Solution structure of a conserved domain of antizyme: a protein regulator of polyamines. Biochemistry 44(35): 11777-11785. 48. Ichiba, T., et al. (1994). Functional regions of ornithine decarboxylase antizyme. Biochem Biophys Res Commun 200(3): 1721-1727. 49. Li, X. and P. Coffino (1994). Distinct domains of antizyme required for binding and proteolysis of ornithine decarboxylase. Mol Cell Biol 14(1): 87-92. 50. Mamroud-Kidron, E., et al. (1994). A unified pathway for the degradation of ornithine decarboxylase in reticulocyte lysate requires interaction with the polyamine-induced protein, ornithine decarboxylase antizyme. Eur J Biochem 226(2): 547-554. 51. Mangold, U. (2005). The antizyme family: polyamines and beyond. IUBMB Life 57(10): 671-676. 52. Mangold, U. and E. Leberer (2005). Regulation of all members of the antizyme family by antizyme inhibitor. Biochem J 385(Pt 1): 21-28. 53. Mitchell, J. L., et al. (1994). Feedback repression of polyamine transport is mediated by antizyme in mammalian tissue-culture cells. Biochem J 299 ( Pt 1): 19-22. 54. Suzuki, T., et al. (1994). Antizyme protects against abnormal accumulation and toxicity of polyamines in ornithine decarboxylase-overproducing cells. Proc Natl Acad Sci U S A 91(19): 8930-8934. 55. Hoshino, K., et al. (2005). Polyamine transport by mammalian cells and mitochondria: role of antizyme and glycosaminoglycans. J Biol Chem 280(52): 42801-42808. 56. Murai, N., et al. (2003). Identification of nuclear export signals in antizyme-1. J Biol Chem 278(45): 44791-44798. 57. Gritli-Linde, A., et al. (2001). Nuclear translocation of antizyme and expression of ornithine decarboxylase and antizyme are developmentally regulated. Dev Dyn 220(3): 259-275. 58. Schipper, R. G., et al. (2004). Intracellular localization of ornithine decarboxylase and its regulatory protein, antizyme-1. J Histochem Cytochem 52(10): 1259-1266. 59. Ivanov, I. P., et al. (1998). A second mammalian antizyme: conservation of programmed ribosomal frameshifting. Genomics 52(2): 119-129. 60. Murai, N., et al. (2009). Subcellular localization and phosphorylation of antizyme 2. J Cell Biochem 108(4): 1012-1021. 61. Zhu, C., et al. (1999). Antizyme2 is a negative regulator of ornithine decarboxylase and polyamine transport. J Biol Chem 274(37): 26425-26430. 62. Chen, H., et al. (2002). Structural elements of antizymes 1 and 2 are required for proteasomal degradation of ornithine decarboxylase. J Biol Chem 277(48): 45957-45961. 63. Snapir, Z., et al. (2009). Antizyme 3 inhibits polyamine uptake and ornithine decarboxylase (ODC) activity, but does not stimulate ODC degradation. Biochem J 419(1): 99-103, 101 p following 103. 64. Ivanov, I. P., et al. (2000). Discovery of a spermatogenesis stage-specific ornithine decarboxylase antizyme: antizyme 3. Proc Natl Acad Sci U S A 97(9): 4808-4813. 65. Tosaka, Y., et al. (2000). Identification and characterization of testis specific ornithine decarboxylase antizyme (OAZ-t) gene: expression in haploid germ cells and polyamine-induced frameshifting. Genes Cells 5(4): 265-276. 66. Murakami, Y., et al. (1996). Cloning of antizyme inhibitor, a highly homologous protein to ornithine decarboxylase. J Biol Chem 271(7): 3340-3342. 67. Nilsson, J., et al. (2000). Antizyme inhibitor is rapidly induced in growth-stimulated mouse fibroblasts and releases ornithine decarboxylase from antizyme suppression. Biochem J 346 Pt 3: 699-704. 68. Chen, L., et al. (2013). Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat Med 19(2): 209-216. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51299 | - |
| dc.description.abstract | 中文摘要
多胺類化合物(polyamines)為一群在生物體內帶有二個以上正電荷的有機分子,因著帶多價正電的性質,此類物質得以藉由靜電作用力與帶負電之核酸、去氧核醣核酸、脂質、或是蛋白表面酸性胺基酸分佈較多的區域結合,可影響細胞之生長及凋亡。由於多胺的過量表現與惡性腫瘤生成息息相關;因此其濃度受到嚴密的調控。而影響多胺生合成 的速率決定步驟酵素 Onithine decarboxylase (ODC) 於體內的活性高低,是主導生物體內多胺類含量的關鍵因子。當細胞內的多胺含量過高時,會促進抗酶蛋白 (Antizyme, Az) mRNA 發生＋1 的轉譯框架位移(+1 frameshift),使全長的 Az 得以合成。Az 能與 ODC 形成異質二聚體 (Heterodimer) ,而阻止 ODC 形成具有催化活性的同質二聚體 (Homodimer) , Az 與 ODC 所形成的複合體可以在不需泛素 (Ubiquitin) 參與的情況下,被 26S 蛋白酶體 (26S proteasome) 辨認,並造成 ODC 的降解。另外, Az 也能阻斷細胞對外來多胺的攝取,因此, Az 是多胺生合成的負調控因子。而人類基因體中帶 有三種Az亞型,其中的第一亞型 (Az1) 與第二亞型 (Az2) 在組織中的分布很相似,且具有極高度的序列相似性。 但在 in vitro 的實驗中卻發現僅有 Az1 具備讓 ODC 降解的能力,而 Az2 的功能為暫時性地抑制 ODC 的活性。 除此之外,生物體內尚有抗酶抑制因子 (Antizyme inhibitor; AzIN) 能夠與 Az 競爭結合 ODC 的位置,形成 Az 及 AzIN 的異質二聚體,使ODC的活性回覆。Az 結合並可提高 AzIN 的穩定性,減少了泛素參之 AzIN 的降解,達成ODC的正向調節。最近的研究結果顯示,人類惡性肝癌 HCC (Human Hepatocellular Carcinoma) 中發現了 AzIN 之 mRNA 會經 ADAR1 (Adenosine Deaminase Acting on RNA-1) 自發性地 mRNA 編輯(mRNA editing),導致在 AzIN 胺基酸序列第367的絲胺酸被甘胺酸取代,而這樣的結果,會使得 AzIN 對 Az1的親和力上升,增加了 Az1 及 AzIN 複合體的穩定性，導致細胞中 ODC 及多胺含量上升，進而誘發細胞的癌化。 本實驗室一直以來希望藉結構的角度來觀察 Az 分別與 ODC 和 AzIN ii 之間交互作用的異同,日前我們已解出了解析度達 2.6 A 的 ODC-Az1 晶體結構,且初步得到 Az1110-228-AzIN 較低解析度 (5.8 A) 的晶體結構,本研究的動機為獲得品質更好的 Az-AzIN 晶體,以更深入的了解 Az1-AzIN 的結構及兩者之間交互作用的細節。因此本研究中所使用的策略為：利用 Az2 與 Az1 的高同源性,及 Az1 -AzINS367G 較高的複合體穩定性;希望能幫助我們得到較高解析度的晶體。 本實驗使用了一系列 Az2 重組蛋白與 AzIN 的表達質體,及一系列 Az1 重組蛋白與 AzINS367G 的表達質體,經表現後藉管柱純化獲得相當純度的蛋白複合體。目前雖然 Az2 系列的重組蛋白與 AzIN 的複合體尚未獲得適當晶體生成的條件。但已可初步地得到 Az1119-228-AzINS367G 複合體的結晶條件。未來將再嘗試著獲得其他複合體的晶體生成條件、及品質更好的晶體,以利後續結構的解析。 | zh_TW |
| dc.description.abstract | Abstract
Polyamines are multivalent organic polycations ubiquitously present in eukaryotic cells. With their polycationic characteristics, polyamines can bind to proteins and nucleic acids via electrostatic interactions to modulate their structures and functions, in turn affecting cell growth and differentiation. However, abberant accumulation of polyamines is linked to tumorigenesis, thus the intracellular concentrations of polyamines are tightly regulated. The activity of ornithine decarboxylase (ODC), the rate-limiting enzyme of the polyamine biosynthesis pathway, can regulate the polyamines abundance in cells. Expression of full-length Az (Antizyme) is increased in response to high cellular polyamines levels through the polyamine-induced translational +1 frameshifting mechanism. Az can block the formation of catalytically active ODC homodimer by forming an Az-ODC heterodimer, which not only inhibits ODC enzymatic activity but also trigger ODC degradation via the 26s proteasome in an ubiquitin-independent manner. Furthermore, Az also inhibits the uptake of extracellular polyamine to reduce the cellular polyamide level. Therefore, Az is a negative regulator of cellular polyamines. In mammals, the Az family is consisted of three members (isoforms 1~3). Among them, isoform 1(Az1) and 2 (Az2) exhibit a similar tissue distribution and high sequence similarity. However, previous studies have shown that only Az1 can efficiently promote ODC degradation in vitro and Az2 most likely functions as a reservoir for transient and reversible suppression of ODC activity. In contrast, AzIN can effectively replenish ODC activity by competing with ODC for Az1 via the formation Az-AzIN heterodimer, which also prolongs the half-life of iv AzIN by preventing its ubiquitination. A recent study show that an mRNA-editing event mediated by the ADAR1 (Adenosine Deaminase Acting on RNA-1) on AzIN mRNA can promote HCC (Human Hepatocellular Carcinoma) by causing a serine-to-glycine substitution at residue 367 of AzIN. The mutated AzIN (AzINS367G) exhibits a higher affinity toward Az, producing a Az1-AzINS367G protein complex with enhanced stability. To understand the structural details regarding the formation of Az1-AzIN complex, our laboratory has determined the crystal structure of a truncated Az1 in complex with ODC and obtained a lower resolution 5.8 A crystal structure of Az1110-228-AzIN. The main objective of this work is to obtain crystal structures of Az-AzIN at higher resolution and elucidate the interactions between Az1 and AzIN in atomic detail. Toward this goal, two strategies were proposed: (1) obtaining a higher resolution crystal structure of Az2-AzIN by exploting the high similarity between Az1 and Az2 and (2) using the more stable of Az1-AzINS367G complex for structural analysis. We have constructed a series of recombinant expression vectors for producing Az2-AzIN and Az1-AzINS367G. The reconstituted complexes were purified by using immobilized metal affinity, ion exchange and gel filtration chromatography for crystallization trials. We have successfully identified a condition by which Az1119-228-AzINS367G can be crystallized. However, like the previous Az1110-228-AzIN crsytals produced previously, these crystals diffract only to low resolution. The attemps for crystallzing Az2-AzIN is not yet successful at this time. We will examine whether the diffraction quality of the Az1119-228-AzINS367G crystals can be further improved and continue to search for new crystallization conditions for Az2-AzIN in the future. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T13:29:50Z (GMT). No. of bitstreams: 1 ntu-105-R00442013-1.pdf: 3540344 bytes, checksum: a8a13abea34e030b14e20cc5779f1c3e (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | 目錄
謝誌 i 中文摘要 iii Abstract v 內文目錄 vii 圖目錄 xi 表目錄 xiv 縮寫表 xv 一、前言 1 1-1 多胺(Polyamine) 1 1-1-1 多胺之生理功能及重要性 1 1-1-2 多胺之生合成代謝途徑 2 1-1-3 多胺之降解 3 1-2 鳥胺酸脫羧酶(Ornithine decarboxylase, ODC) 4 1-2-1 鳥胺酸脫羧酶之生理功能及催化機制 4 1-2-2 鳥胺酸脫羧酶之結構 4 1-2-3 鳥胺酸脫羧酶與疾病之關係 5 1-2-4 鳥胺酸脫羧酶之降解機制 5 1-3 抗酶 (antizyme, Az) 7 1-3-1 抗酶之生理功能簡介 7 1-3-2 抗酶之結構 8 1-3-3 抗酶之種類及特性 8 1-3-4 抗酶與鳥胺酸脫羧酶之交互作用 9 1-4 抗酶抑制因子 (antizyme inhibitor, AzIN) 10 1-4-1 抗酶抑制因子之生理功能 10 1-4-2 抗酶抑制因子之結構 10 1-4-3 抗酶抑制因子與抗酶之交互作用 11 1-4-4 抗酶抑制因子突變與疾病之關係 11 1-5 研究目的 11 二、材料與方法 13 2-0 蛋白表現量之測試 13 2-1 Az-AzIN 蛋白複合體之共表達 13 2-1-1 Az257-189-AzIN1-437 蛋白複合體之共表達 15 2-1-2 Az264-189 -AzIN1-437蛋白複合體之共表達 17 2-1-3 Az275-189-AzIN1-437 蛋白複合體之共表達 18 2-1-4 Az195-228-AzIN1-437,S367G 蛋白複合體之共表達 19 2-1-5 Az1110-228-AzIN1-437,S367G 蛋白複合體之共表達 20 2-1-6 Az1119-228-AzIN1-437,S367G 蛋白複合體之共表達 21 2-2 蛋白純化 22 2-2-1 Az257-189-AzIN1-437 蛋白複合體之純化 22 2-2-2 Az264-189 -AzIN1-437蛋白複合體之純化 25 2-2-3 Az275-189-AzIN1-437 蛋白複合體之純化 25 2-2-4 Az195-228-AzIN1-437,S367G 蛋白複合體之純化 26 2-2-5 Az1110-228-AzIN1-437,S367G 蛋白複合體之純化 26 2-2-6 Az1119-228-AzIN1-437,S367G 蛋白複合體之純化 26 2-3 蛋白之定量 26 2-4 蛋白晶體培養 27 2-4-1 預結晶試劑 27 2-4-2 蛋白結晶條件篩選 27 2-4-3 養晶條件微調 28 三、結果 29 3-0 Az2-AzIN 蛋白複合體 29 3-1 Az2-AzIN 蛋白複合體不同組合之小量表現 29 3-2 Az2-AzIN 蛋白複合體之純化及晶體培養 30 3-2-1 Az257-189-AzIN1-437 蛋白複合體之純化 30 3-2-2 Az257-189-AzIN1-437 蛋白複合體之晶體培養 32 3-2-3 Az264-189-AzIN1-437 蛋白複合體之純化 32 3-2-4 Az264-189-AzIN1-437 蛋白複合體之晶體培養 33 3-3 Az1 -AzIN1-437,S367G 的蛋白複合體小量表現 34 3-4 Az1 -AzIN1-437,S367G 複合體不同組合菌落暨誘導溫度之小量表現 34 3-5 Az1 -AzIN1-437,S367G 蛋白複合體之純化及晶體培養 35 3-5-1 Az195-228-AzIN1-437,S367G 蛋白複合體之純化 35 3-5-2 Az195-228-AzIN1-437,S367G 蛋白複合體之晶體培養 36 3-5-3 Az1110-228-AzIN1-437,S367G 蛋白複合體之純化 36 3-5-4 Az1110-228-AzIN1-437,S367G 蛋白複合體之晶體培養 37 3-5-5 Az1119-228-AzIN1-437,S367G 蛋白複合體之純化 38 3-5-6 Az1119-228-AzIN1-437,S367G 蛋白複合體之晶體培養 38 四、討論 40 圖 47 表 83 參考文獻 86 | |
| dc.language.iso | zh-TW | |
| dc.subject | 人類抗? | zh_TW |
| dc.subject | 人類抗? | zh_TW |
| dc.subject | human antizyme | en |
| dc.subject | human antizyme | en |
| dc.title | 人類抗酶與抗酶抑制蛋白複合體之結構研究 | zh_TW |
| dc.title | Structural studies of human antizyme isoforms
in complex with its inhibitor | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 曾秀如,徐駿森 | |
| dc.subject.keyword | 人類抗?, | zh_TW |
| dc.subject.keyword | human antizyme, | en |
| dc.relation.page | 91 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2016-02-04 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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| 檔案 | 大小 | 格式 | |
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| ntu-105-1.pdf 未授權公開取用 | 3.46 MB | Adobe PDF |
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