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論文中文名稱:以分子動態模擬探討鋅離子對c-Cbl RING domain結構穩定性的影響 [以論文名稱查詢館藏系統]
論文英文名稱:Molecular Dynamics Simulations to Investigate the Effects of Zinc Ions on the Structural Stability of the c-Cbl RING Domain [以論文名稱查詢館藏系統]
院校名稱:臺北科技大學
學院名稱:工程學院
系所名稱:化學工程研究所
出版年度:97
中文姓名:楊清濤
英文姓名:Ching-Tao Yang
研究生學號:94738028
學位類別:碩士
語文別:英文
口試日期:2008-01-04
論文頁數:85
指導教授中文名:劉宣良
指導教授英文名:Hsuan-Liang Liu
口試委員中文名:方旭偉;蔡偉博
口試委員英文名:Hsu-Wei Fang;Wei-Bor Tsai
中文關鍵詞:泛素化E1E2E3RING domain鋅離子c-Cbl domain金屬離子螯合點
英文關鍵詞:ubiquitylationE1E2E3RING domainzinc ionc-Cbl domainmetal ion binding site
論文中文摘要:在真核生物中,蛋白質的泛素化過程靠著泛素活化酶(E1)、泛素轉移酶(E2)、以及泛素連接酶(E3)扮演著調節多樣性生化程序的重要角色。其中,泛素連接酶是賦予泛素化專一性以及將泛素轉移至特殊待降解的目標蛋白上的重要關鍵之ㄧ。RING型泛素連接酶上的RING domain是需要鋅離子輔助形成其三級摺疊的小型結構蛋白。於本研究中,我們利用c-Cbl RING domain在不同條件下的分子動態模擬來詳細呈現其結構完整性與鋅離子之間的關係。模擬結果顯示鋅離子確實對維持c-Cbl RING domain的三級與二級結構穩定具有相當重要的貢獻。模擬結果進一步展現c-Cbl RING domain二級結構的穩定性是由金屬離子螯合點內或附近的氫鍵網絡所決定的。我們也論證鋅離子螯合在第二個金屬螯合點對於提升c-Cbl RING domain結構的完整性的貢獻比第一個金屬離子螯合點更多。接著進一步研究c-Cbl、CNOT4、以及p44的RING domain於模擬過程中的結構特色,我們發現p44上的recognition site的穩定性明顯低於c-Cbl以及CNOT4,而整體三級與二級結構穩定性卻無顯著差異。除此之外,c-Cbl以及CNOT4的兩個金屬螯合點之間的結構特性也分別與p44明顯不同。由此,我們推論具有E3功能的RING domain必須具有一個高度穩定的recognition site。雖然仍需要更多證據來證實我們的推論,不過本研究結果與前人實驗結果仍呈現良好的一致性。
論文英文摘要:In eukaryotic cells, ubiquitylation of proteins plays a critical role in regulating diverse cell processes by the ubiquitin activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin protein ligase (E3). The E3 enzymes are the key component that confers specificity to the ubiquitylation process and directs the conjugation of ubiquitin to the specific target protein. The RING domains are small structured protein domains that require the coordination of zinc ions for a stable tertiary fold and some of them are involved in RING E3s. In this study, we reported detailed relationships between the structural integrity of the c-Cbl RING domain and the two zinc ions under various conditions by molecular dynamics simulations. Our results showed that these two zinc ions indeed play an important role in maintaining the stability of both secondary and tertiary structures of the c-Cbl RING domain. Furthermore, our results also reveal that the secondary structural stabilities of the c-Cbl RING domain are mainly determined by the hydrogen bond networks in or near the stable metal ion binding site. Our results also demonstrate that the zinc ion binding site 2 (S2) contributes more significantly on the structural integrity of c-Cbl RING domain comparing to S1. Sequentially, we investigated the structural features of the RING domains of c-Cbl, CNOT4, and p44 using MD simulations. Several interesting features were observed. For example, the stability of recognition site of p44 is greatly lower than of that of c-Cbl and CNOT4. However, there are no significant differences between the tertiary or secondary structural stability of p44, c-Cbl, and CNOT4. Moreover, the structural features of the two zinc ion binding sites of p44 are different from those of c-Cbl, and CNOT4. Therefore, we suggested that the recognition site with high structural stability is a fundamental requirement for a RING domain to function as E3 ligases. Although more experimental evidences are required to reinforce our hypothesis, our results are in good agreement with the results from the previous experimental and computational studies.
論文目次:ABSTRACT i
ACKNOWLEDGEMENT v
CONTENTS vi
TABLE CONTENTS ix
FIGURE CONTENTS x
Chapter 1 GENERAL INTRODUCTION 1
Chapter 2 LITERATURE REVIEW 2
2.1 A Introduction of RING Domain 2
2.1.1Events and History of Discovery 2
2.1.2 Biological Function 3
2.1.3 Amino Acid Sequence and Topology 5
2.1.4 Activity Test, Protein Production, Purification, and Molecular Characterization 6
2.2 Metal Content 7
2.2.1 Metal Ion Binding Site Geometries 8
2.2.2 Spectroscopic and Metal Binding Properties of RING Domains 11
2.3 X-ray and NMR Structures of RING Finger Domains 12
2.3.1 Structures of Related Domains 15
2.3.2 Structures of the RING Domains in Complex with other Proteins 18
2.4 Cbl Protein Family 20
2.4.1 A Brief Introduction of c-Cbl Protein 21
2.4.2 The c-Cbl-UbcH7 Complex 22
2.4.3 The c-Cbl RING Domain 24
2.4.4 The SCF Ubiquitin Ligase Complex 24
2.5 Research Objectives 26
Chapter 3 MOLECULAR DYNAMICS SIMULATIONS 27
3.1 Overview 27
3.1.1 The Importance of Molecular Dynamics Simulations 27
3.1.2 A Brief Introduction of Molecular Dynamics 29
3.1.3 The Role of Solvent in Protein Dynamics 29
3.2 Force Fields 31
3.2.1 The Parameters in the Force Field 35
3.3 Minimization 35
3.3.1 Minimization Algorithms 38
3.4 Molecular Dynamics 40
3.4.1 Protein Folding 41
3.4.2 Constraints During Dynamics Simulations 43
3.4.2.1 The NVE Ensemble 43
3.4.2.2 The NVE Ensemble 43
3.4.3 Temperature Jump Techniques 44
3.4.4 Dynamics 45
3.4.4.1 The Requirements for Performing a MD Simulation 46
3.5 Structural Analysis 47
Chapter 4 Molecular Dynamics Simulations to Investigate the Effects of Zinc Ions on the Structural Stability of the c-Cbl RING Domain 50
4.1 Abstract 50
4.2 Introduction 51
4.3 Methods 54
4.3.1 The construction of the c-Cb1 RING domain structures associated with four zinc ion binding states 54
4.3.2 Molecular dynamics simulations 54
4.3.3 Structural analysis 55
4.4 Results and Discussion 57
4.4.1 The effects of the two zinc ions on the tertiary structural stability of the c-Cbl RING domain 57
4.4.2 The effects of zinc ions on the secondary structural stability of the c-Cbl RING domain 65
4.5 Conclusions 68
4.6 Acknowledgements 69
4.7 References 69
Chapter 5 GENERAL CONCLUSIONS 73
Chapter 6 GENERAL REFERENCES 76
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