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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張鑫 | |
dc.contributor.author | Ren-You Pan | en |
dc.contributor.author | 潘仁宥 | zh_TW |
dc.date.accessioned | 2021-06-15T02:50:47Z | - |
dc.date.available | 2014-09-15 | |
dc.date.copyright | 2009-09-15 | |
dc.date.issued | 2009 | |
dc.date.submitted | 2009-08-05 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/44318 | - |
dc.description.abstract | C型肝炎病毒帶有一單股正向的RNA基因體,可編碼出一條多蛋白質前驅物並藉由宿主和病毒的蛋白酶切割成具有功能性的蛋白質,其中非結構性蛋白質NS3具有631個胺基酸,擁有serine protease和RNA helicase的功能。先前實驗室已證實,NS4A可作為NS3 protease的輔因子,幫助NS3進行病毒多蛋白質切割以及NS3內部截切,而且此NS3內部截切功能可由不同的NS3分子藉由trans的方式達成。由一系列的NS4A單一點突變的研究指出,NS4A的Ile-25、Val-26、Ile-29這三個胺基酸對於NS3內部截切和細胞轉型能力是重要的。
由於NS3可以trans的方式去切割另一個NS3分子,因此本論文首先藉由SPDB viewer軟體由結構上預測NS3分子間可能會產生交互作用的胺基酸,進行刪除與點突變,分析這些改變對NS3分子間交互作用的影響,也分析它們在內部截切功能上的重要性。由共同免疫沉澱的結果顯示,一個NS3分子的NTPase domain會和另一個NS3分子的RNA binding domain產生交互作用形成複合體;當NTPase domain和RNA binding domain內的胺基酸發生定點突變時,會降低NS3內部截切的效率。另一方面,為瞭解NS3在多蛋白質切割及NS3內部截切兩種proteolytic cleavage作用機制上的差異性,首先藉由NS3的刪除突變分析兩種切割作用所需的NS3片段,結果發現NS3的protease domain NS3(1-181) 雖保有病毒多蛋白質切割的能力,但卻不具有NS3內部截切的功能;然而將片段延伸到擁有ATP-binding domain長度的NS3蛋白質,包含NS3(1-223)、NS3(1-313)、NS3(1-369)、NS3(1-402)、NS3(1-462) 以及全長的NS3,就同時具有多蛋白質切割和NS3內部截切能力,顯示了NS3蛋白質在病毒多蛋白質切割及NS3內部截切的作用機制上的差異性。另外也發現NS4A可以幫助NS3(1-402) 執行NS3內部截切能力,而且和NS3全長一樣,當NS4A的Ile-25、Val-26或Ile-29胺基酸產生突變時則無法進行此內部截切。由細胞聚落形成分析的結果發現,NS3內部截切的自然產物NS3(1-402) 相較於全長的NS3來說,具有較高的細胞轉型能力,而且其蛋白酶活性對於細胞轉型能力是重要的,推測NS3內部截切作用對於細胞癌化有重要的影響。 | zh_TW |
dc.description.abstract | Hepatitis C virus (HCV) possesses a single-stranded positive-sense RNA genome, the genomic RNA encodes the viral polyprotein precursor that can be further processed by host and the viral proteases to form functional proteins. The nonstructural protein 3 (NS3) has 631 amino acids and possesses serine protease and RNA helicase activities. NS4A is a cofactor of the NS3 protease. Previous study has shown that NS4A can support NS3 in the viral polyprotein processing and internal NS3 cleavage. In addition, the internal NS3 cleavage can occur in trans. Further mutational analysis demonstrated that the Ile-25, Val-26, and Ile-29 residues of the NS4A protein are important for the NS4A-dependent internal NS3 cleavage and the transforming activity of NS3.
Since internal NS3 cleavage can occur in trans, amino acid residues participated in the interaction between two NS3 molecules were predicted in this study by using the SPDB viewer software. The analysis revealed a potential interaction between the NTPase domain and the RNA binding domain of the NS3 protein. The interaction was confirmed by co-immunoprecipitation. In addition, NS3 mutants with amino acid substitutions at the predicted interacting residues showed a reduced efficiency of internal NS3 cleavage. Furthermore, in order to understand the mechanisms that differ between the polyprotein processing and internal NS3 cleavage, the minimum length of the NS3 protein required for these two proteolytic cleavage were analyzed. The NS3 protease domain, NS3(1-181), demonstrated a polyprotein processing activity, but failed to cleave NS3 internally. Nevertheless, NS3 proteins NS3(1-223)、NS3(1-313)、NS3(1-369)、NS3(1-402)、NS3(1-462) and the full length NS3 that retain the ATP-binding motif in the helicase domain have both the polyprotein processing and internal NS3 cleavage activities, indicating that the mechanisms of NS3 involved in these two proteolytic cleavages are different. In addition, amino acid substitutions at the I25, V26 and I29 of the NS4A protein abolished the internal cleavage of NS3(1-402) similar to that of the full length NS3. Furthermore, colony formation assay demonstrated a higher transforming activity of the natural product of internal NS3 cleavage, NS3(1-402), than the full length NS3. The serine protease activity of NS3 has a critical role in the degree of colony formation. Taken together, these results indicate that the internal NS3 cleavage plays an important role in the transforming activity. | en |
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dc.description.tableofcontents | 摘要……………………………………………………………………………... i
Abstract………………………………………….……………………………… iii 目錄……………………………………………………………………………... v 表格目錄…………………………………………………………………...…… viii 圖目錄…………………………………………………………………………... ix 第一章 緒論…………………………………………………………................. 1 一、C型肝炎病毒的發現與分類…………………………………........... 1 二、C型肝炎病毒相關的肝病變與治療………………………………... 1 三、C型肝炎病毒的基因體構造及功能……………………………….. 2 四、C型肝炎病毒非結構性蛋白質NS3的特性………………………. 5 五、C型肝炎病毒非結構性蛋白質NS4A的特性……………...……… 7 第二章 研究目的………………………………………………………..……... 10 第三章 材料與方法…………………………..…………………………..…..... 11 一、化學藥品及試劑…………………….…………………………..…... 11 二、酵素………………………………………………………………...... 12 三、抗體………………………………………………………………..… 13 四、細胞培養液及轉染試劑…………………………………………..… 13 五、套組試劑…………………………………………………………..… 13 六、其它………………………………………………………………...… 14 七、細胞株……………………………………………………………….. 14 八、實驗室提供的質體………………………………………………...… 15 九、質體的建構………………………………………………………….. 17 十、細菌轉型 (Transformation)…………………………………...…….. 18 十一、DNA轉染 (DNA transfection)…………………………...……… 19 十二、細胞全蛋白質之收取………………………………………...…… 20 十三、蛋白質定量…………………………………………….......……… 20 十四、正十二烷硫酸鈉-聚丙醯胺板膠電泳 (SDS-polyacrylamide gel electrophoresis, SDS-PAGE)……………………………….........……….. 21 十五、西方墨點法……………………………………………...………… 22 十六、共同免疫沉澱法…………………………………………...……… 23 十七、柔軟瓊脂中細胞聚落形成分析 (Soft agar colony formation assay)……………………………………………………………………… 23 第四章 實驗結果…………………..................................................................... 24 一、NS3蛋白質分子間的交互作用………………..…………………… 24 二、NS3的催化三元體對於其蛋白酶活性的影響..…………………… 25 三、NS3刪除突變的內部截切能力………………..…………………… 26 四、NS3p蛋白質具有多蛋白質切割能力………………………………. 27 五、不同長度的NS3蛋白質區段對於細胞轉型能力的影響……….… 28 六、不同點突變的NS4A對於NS3(1-402) 執行NS3內部截切作用的影響……………………………………………………………………….. 28 第五章 討論……………………………………………………………........... 30 一、NS3蛋白質二聚體的形成………….………………………………. 30 二、參與NS3蛋白質分子間交互作用的胺基酸…………………….… 30 三、N-terminal domain of NS3 RNA helicase在多蛋白質切割以及內部截切作用扮演著不同的角色…………………………………………….. 31 四、NS3(1-402) 所引起的細胞轉型能力……………………………….. 33 五、由結構學的角度解釋NS3和NS4A在病毒多蛋白質切割以及NS3內部截切上扮演不同角色的原因……………………………………….. 34 附表……………………………………………….…………………………… 35 附圖..…………………………………………………………………………... 39 參考文獻..……………………………………………………………………... 53 | |
dc.language.iso | zh-TW | |
dc.title | C型肝炎病毒非結構性蛋白質NS3內部截切的分子機制 | zh_TW |
dc.title | Molecular mechanisms involved in the internal NS3 cleavage of hepatitis C virus | en |
dc.type | Thesis | |
dc.date.schoolyear | 97-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 鄧述諄,董馨蓮,詹迺立 | |
dc.subject.keyword | C型肝炎病毒,非結構性蛋白質NS3,內部截切作用,細胞轉型能力, | zh_TW |
dc.subject.keyword | Hepatitis C virus,nonstructural protein NS3,internal NS3 cleavage,transforming activity, | en |
dc.relation.page | 60 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2009-08-05 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 微生物學研究所 | zh_TW |
顯示於系所單位: | 微生物學科所 |
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ntu-98-1.pdf 目前未授權公開取用 | 1.5 MB | Adobe PDF |
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