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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳平(Richard Ping Cheng) | |
| dc.contributor.author | Chin-Yih Chen | en |
| dc.contributor.author | 陳清怡 | zh_TW |
| dc.date.accessioned | 2021-06-16T03:52:30Z | - |
| dc.date.available | 2015-02-04 | |
| dc.date.copyright | 2015-02-04 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-01-14 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/55233 | - |
| dc.description.abstract | 離胺酸乙醯化是在生物體內非常普遍的轉譯後修飾,並參與了許多重要的生 物功能。其反應是將離胺酸側鏈上的胺基所帶的正電荷藉由裝上乙醯基而中和, 此步驟調控許多具有離胺酸的蛋白質內的生化反應。在此研究中,我們設計可偵 測蛋白質二級結構的胜肽模型來測量離胺酸乙醯化對於蛋白質二級結構的影響。 α-螺旋用圓二色光譜儀來測定其螺旋程度。β-摺板則用超導核磁共振光譜儀來觀測 其摺板程度。結果顯示,相對於離胺酸,乙醯化離胺酸可增加α-螺旋的螺旋性質, 也可增進β-摺板的穩定度。乙醯化離胺酸相對於離胺酸,能穩定蛋白質二級結構。
在乙醯化離胺酸生物功能上的研究,我們選用人類免疫缺乏病毒 Tat 蛋白質,它是一個乙醯化離胺酸調節的核糖核酸結合蛋白。我們研究 Tat 蛋白中一段胜 肽序列:Tat49-57,具有與病毒 TAR RNA 結合及穿透細胞膜的能力。Tat49-57 上帶有 許多正電荷的胺基酸,其中的兩個離胺酸(50 號和 51 號位置)都可以在生物體內 被乙醯化酶催化成乙醯化離胺酸。此研究將 Tat49-57上的兩個離胺酸分別以乙醯化 離胺酸取代,來觀察他們對 TAR RNA 結合及穿透細胞膜能力的影響。利用膠體電 泳偏移分析來研究Tat衍生胜肽與TAR RNA的解離常數。同時也以圓二色光譜儀 偵測Tat衍生胜肽的結構。利用流式細胞儀測量Tat衍生胜肽進入Jurkat細胞內部 的效率。結果顯示,乙醯化離胺酸會降低 TAR RNA 結合及穿透細胞膜的能力,且 在 Tat49-57 中,取代 50 號位置的離胺酸成乙醯化離胺酸在 TAR RNA 結合及穿透細 胞膜的能力損壞的程度都比取代 51 號位置的離胺酸成乙醯化離胺酸還要嚴重,顯 示 Tat49-57 中 50 號位置離胺酸是個可能對功能來說相對重要的位置。 | zh_TW |
| dc.description.abstract | Lysine acetylation is a very common and highly regulated post-translational
modification (PTM) and is crucial for the protein structures and many biological functions in living organisms. The main effect of lysine acetylation is the neutralization of the lysine positive charge and consequently the regulation of the biochemical properties of lysine-containing proteins. The roles of lysine acetylation in cellular functions have been studied extensively. However, the effect of acetylation on protein secondary structures remains unclear. To study the effect of lysine acetylation on protein secondary structures, α-helical monomeric peptides and β-hairpin peptides were designed as basic models and acetyl-Lysine (AcK) was introduced into each guest position. Hydrogen-bonds have significant impact on protein stability, therefore the effect of replacing a methyl group with an amine group in acetylated Lys residues on secondary structure stability was also studied. The helical content of the α-helical peptides were determined by circular dichorism spectroscopy (CD), and the β-hairpin peptides were analyzed by NMR spectroscopy (TOCSY , ROESY , NOESY , DQF-COSY) to determine the sheet propensity. The result showed that compared to Lys, Lys acetylation increased both α-helix and β-sheet stability. In an α-helix, AcK increased the helix propensity, but lowered the C-Cap parameters. In a β-hairpin, the folding percentage of HPTAcKAla was 1.2 fold higher than that of HPTLysAla. Post-translational modification of RNA binding proteins (RBPs) plays an important role in regulating many cellular functions. The Tat protein, one of the RBPs, is essential for the life cycle of HIV-1 and is known to undergo acetylation on specific lysines to modulate various Tat functions. Tat, like most of the RBPs, contain a region (Tat49-57) rich in positively charged amino acids such as Arg and Lys to mediate the initial recognition of the negatively charged phosphate backbone RNA and the efficiency of cellular uptake. To investigate the effect of Lys side chain charge on RNA recognition and on cellular uptake, each positively charged Lys in Tat49-57 was replaced with one AcK at a time. The dissociation constant for the binding affinity of TAR RNA-Tat derived peptide was studied by gel shift assays, and the cellular uptake efficiency for peptide-treated Jurkat cells was assessed by flow cytometry. The result showed that removing the Lys positive charge by lysine acetylation affected RNA recognition and cell penetration of HIV-1 Tat. Furthermore, the effects showed position dependence. Acetylation of Lys 50 and 51 decreased the binding affinity between Tat49-57 and TAR RNA and could not be recovered by introducing hydrogen bond donors. Acetylation of Lys 50 and 51 on Tat49-57 decreased the cell penetration efficiency. However, adding hydrogen bond donors could compensate this decrease. | en |
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| dc.description.tableofcontents | Table of Content
口試委員會審定書 .......................................................................................................... ii 誌謝................................................................................................................................ iii 中文摘要 ......................................................................................................................... iv Abstract .............................................................................................................................. v Table of Content ............................................................................................................. vii List of Figures .................................................................................................................. ix List of Tables ................................................................................................................. xiii List of Schemes ............................................................................................................. xiv Abbreviations ................................................................................................................... xv Chapter 1 .......................................................................................................................... 1 1-1. Central Dogma of Molecular Biology ........................................................... 2 1-2. Proteins .......................................................................................................... 2 1-3. Peptide conformation ..................................................................................... 3 1-4. Four levels of protein structure ...................................................................... 5 Primary structure ............................................................................................ 5 Secondary structure ........................................................................................ 5 Tertiary structure ............................................................................................ 6 Quaternary structure ...................................................................................... 7 1-5. Driving Forces for Protein Folding ............................................................... 7 Electrostatic interactions ................................................................................ 7 Hydrogen bonding .......................................................................................... 8 van der Waals interactions ............................................................................. 8 Hydrophobics .................................................................................................. 8 1-6. Post-translation modification ......................................................................... 9 1-7. Post translational modification in RNA recognition and cell penetration ... 10 1-8. Thesis overview ........................................................................................... 11 References .............................................................................................................. 14 Chapter 2 ........................................................................................................................ 20 2-1. Introduction ..................................................................................................... 22 The propensities of amino acids in secondary structures ............................. 22 Helicity .......................................................................................................... 23 Circular Dichroism spectroscopy ................................................................. 23 Modified Lifson-Roig Theory ........................................................................ 24 β-Sheet stability ............................................................................................ 25 β-hairpin stability .......................................................................................... 25 Lysine Acetylation and Protein Secondary Structures .................................. 26 2-2. Results and Discussion ................................................................................... 27 α-Helical Peptide Design .............................................................................. 27 β-Hairpin Peptide Design ............................................................................. 27 Peptide Synthesis .......................................................................................... 28 Circular Dichroism Spectroscopy and Fraction Helix (fhelix) ....................... 29 β-Hairpin Structure ...................................................................................... 34 Fraction Folded Population and ΔGfold ........................................................ 40 2-3. Conclusion ...................................................................................................... 42 2-5. Acknowledgment ............................................................................................ 43 2-6. Experimental Section ...................................................................................... 43 General Materials and Methods ................................................................... 43 Solid Phase Peptide Synthesis ...................................................................... 44 Ultraviolet-Visible (UV-vis) Spectroscopy ................................................... 53 Circular Dichroism Spectroscopy (CD) ....................................................... 54 NMR spectroscopy and Sequence Specific Assignment ................................ 54 Chemical Shift Deviation .............................................................................. 62 Interproton Distances from NOE Cross Peaks ............................................. 62 Fraction Folded Population and Folding Free Energy (ΔGfold) ................... 63 3JNHα Spin−Spin Coupling ............................................................................ 63 Reference ................................................................................................................ 65 Chapter 3 ........................................................................................................................ 72 3-1. Introduction ..................................................................................................... 74 Human Immunodeficiency Virus (HIV) ........................................................ 74 HIV transcription elongation ........................................................................ 75 Tat-Dependent Transcriptional Elongation .................................................. 77 Tat Regulation by Post-Translational Modifications--- Lysine Acetylation . 78 Transactivator of Transcription (Tat) Protein .............................................. 78 Cell Penetrating Peptides ............................................................................. 79 3-2. Results and Discussion ................................................................................... 81 Peptides Design and Synthesis ...................................................................... 81 Electrophoretic Mobility Shift Assay (EMSA) .............................................. 85 Circular Dichorism Spectroscopy ................................................................. 90 Cellular uptake .............................................................................................. 91 3-3. Conclusion .................................................................................................... 103 3-4. Acknowledgment .......................................................................................... 105 3-5. Experimental section ..................................................................................... 105 General Materials and Methods ................................................................. 105 Peptide Synthesis ........................................................................................ 106 Ultraviolet-Visible (UV-vis) Spectroscopy ................................................. 117 Gel Shift Assay……………………………………………………………………118 Circular Dichroism (CD) Spectroscopy ..................................................... 120 Cellular uptake Assay ................................................................................. 121 Reference .............................................................................................................. 123 List of Figures Figure 1-1. The relationship between DNA, RNA and protein as described in the central dogma. .............................................................................................................................. 2 Figure 1-2. Formation of a peptide bond. ......................................................................... 3 Figure 1-3. The dihedral angles in the backbone of a peptide. ......................................... 4 Figure 1-4. The Ramachandran diagram :31 plot of ψ against φ. The predicted ψ and φ values for α-helix and β-sheet are indicated. ................................................................... 4 Figure 1-5. Structure of (a.) acetyl-lysine and (b.) 2-amino-6-ureido-hexanoic acid. ... 12 Figure 2-1. Circular dichroism spectra of the peptides at pH 7 (273 K) in 1 mM phosphate, borate, and citrate buffer with 1 M NaCl: (A) NCapAcK, NCapAuh and AlaK; (B) CCapAcK, CCapAuh and KAla; (C) KAcK9, KAuh9 and KAla; (D) KAcK9, KAuh9 and KAla. ............................................................................................................ 30 Figure 2-2. Helix propensity (w), N-Capping Parameter (n), and C-Capping Parameter (c) for Lys, AcK and Auh. ............................................................................................... 33 Figure 2-3. The HN-Hα region of the TOCSY spectra for AcK-containing peptides. (A) HPTFAcKAla; (B) HPTAcKAla; (C)HPTUAcKAla. ..................................................... 34 Figure 2-4. The HN-Hα region of the TOCSY spectra for Auh-containing peptides. (A) HPTFAuhAla; (B) HPTAuhAla; (C)HPTUAuhAla. ....................................................... 34 Figure 2-5. The Hα chemical shift deviation for HPTAcKAla and HPTAuhAla. (A)HPTAcKAla; (B)HPTAuhAla; (C) Comparison of Hα chemical shift deviation for HPTAcKAla (red), HPTAuhAla (blue) and HPTLysAla (green). .................................. 35 Figure 2-6. The NOEs illustrations of HPTFAcKAla, HPTFAuhAla, HPTAcKAla HPTAuhAla, HPTUAcKAla and HPTUAuhAla, ........................................................... 38 Figure 2-7. The Wüthrich diagram of folding reference peptides. The thickness of the bands represents the intensity of NOEs. .......................................................................... 39 Figure 2-8. The Wüthrich diagram of experimental reference peptides. The thickness of the bands represents the intensity of NOEs. .................................................................... 39 Figure 2-9. The Wüthrich diagram of unfolding reference peptides. The thickness of the bands represents the intensity of NOEs. .......................................................................... 40 Figure 2-10. The fraction folded of all amino acid residues for HPTAcKAla and HPTAuhAla. .................................................................................................................... 41 Figure 2-11. The comparison of folding percentage and free energy among HPTAcKAla, HPTAuhAla and HPTLysAla. ......................................................................................... 41 Figure 3-1. The structure of HIV. .................................................................................... 74 Figure 3-2. The HIV-1 virus genome. ............................................................................. 76 Figure 3-3. The sequence and secondary structure of HIV-1 TAR RNA from position +17 to +45 containing the bulge and loop regions. ......................................................... 77 Figure 3-4. A summary of two different mechanisms in HIV-1 gene expression: (A) ineffective RNAPII elongation in the absence of Tat; (B) transcription activation mediated by Tat-pTEFb complexes. ................................................................................ 78 Figure 3-5. The exons and regions of the Tat protein. The sequence of the basic region containing the RNA binding site is RKKRRQRRR. ....................................................... 79 Figure 3-6. The chemical structure of 6-carboxy-fluorescein. ........................................ 84 Figure 3-7. Gel images of the electrophoretic mobility shift assay (EMSA) for Tat-derived peptides. All lanes contained 100 nM fluorescein-labeled HIV-1 TAR RNA in the presence of 10 μg/mL bulk E. coli tRNA. ............................................................. 87 Figure 3-8. The global fitting of EMSA results for AcK51Tat(A), AcK50Tat(B), Auh51Tat(C) and Auh50Tat(D) binding to TAR RNA in the presence of 10 μg/mL bulk E. coli tRNA. ................................................................................................................... 87 Figure 3-9. The dissociation constant (KD) of AcK51Tat, AcK50Tat, Auh51Tat and Auh50Tat binding to TAR RNA in the presence of 10 μg/mL bulk E. coli tRNA. ........ 88 Figure 3-10. Images of typical gels of the electrophoretic mobility shift assay (EMSA) for Tat-derived peptides. All lanes contained 100nM fluorescein-labeled HIV-1 TAR RNA in the presence of 10 μg/mL bulk E. coli tRNA. ................................................... 89 Figure 3-11. The global fitting results of peptides Auh49Tat(A), Auh56Tat(B) and Auh57Tat(C) binding to TAR RNA in the presence of 10 μg/mL bulk E. coli tRNA .... 89 Figure 3-12. The apparent dissociation constant of peptides Auh49Tat, Auh56Tat, and Auh57Tat in the presence of 10μg/mL E. coli tRNA. ..................................................... 90 Figure 3-13. CD spectra between 200 and 300 nm of the Tat-derived peptides: (A)AcK50Tat, AcK51Tat, Auh50Tat and Auh51Tat peptides and (B) Auh49Tat, Auh56Tat, Auh57Tat peptides. All of the peptides concentration close to 50 μM in pH 7 buffer (10 mM Tris) and 298K conditions reported in mean residue ellipticity. ............ 91 Figure 3-14. Flow cytometry results showing the side scattered light plotted against the forward scattered light for live control cells, dead control cells, and cells incubated with 7 μM peptides Fl-ArgTat, Fl-AcK51Tat, Fl-AcK50Tat, Fl-Auh51Tat and Fl-Auh50Tat. The gate used to restrict the population of cells analyzed is shown and labeled as P1……..93 Figure 3-15. Flow cytometry results showing the side scattered light plotted against the forward scattered light for live control cells, dead control cells, and cells incubated with 120 μM peptides Fl-ArgTat, Fl-AcK51Tat, Fl-AcK50Tat, Fl-Auh51Tat and Fl-Auh50Tat. The gate used to restrict the population of cells analyzed is shown and labeled as P1………………………………………………………………………………….……93 Figure 3-16. Flow cytometry results showing the PI fluorescence against the FITC fluorescence for live control cells, dead control cells, and cells incubated with 7 μM peptides Fl-ArgTat, Fl-AcK51Tat, Fl-AcK50Tat, Fl-Auh51Tat and Fl-Auh50Tat. The PI threshold used to restrict the population of cells analyzed is shown and labeled as P2....................................................................................................................................94 Figure 3-17. Flow cytometry results showing the PI fluorescence against the FITC fluorescence for live control cells, dead control cells, and cells incubated with 7 μM peptides Fl-ArgTat, Fl-AcK51Tat, Fl-AcK50Tat, Fl-Auh51Tat and Fl-Auh50Tat. The PI threshold used to restrict the population of cells analyzed is shown and labeled as P2....................................................................................................................................94 Figure 3-18. Flow cytometry results for cellular uptake into Jurkat cells in the presence of fetal bovine serum upon incubation with (A) 7 μM Tat-derived peptides and (B) 120 μM Tat-derived peptides for 15 min at 37°C. ................................................................. 95 Figure 3-19. Flow cytometry results showing the fluorescence signal for live control cells, and cells incubated with 7 μM peptides Fl-ArgTat, Fl-AcK51Tat, Fl-AcK50Tat, Fl-Auh51Tat and Fl-Auh50Tat for 15 minutes at 37 oC.……………...……………….95 Figure 3-20. Flow cytometry results showing the fluorescence signal for live control cells, and cells incubated with 120μM peptides Fl-ArgTat, Fl-AcK51Tat, Fl-AcK50Tat, Fl-Auh51Tat and Fl-Auh50Tat for 15 minutes at 37 oC.……………...……………….96 Figure 3-21. Flow cytometry results showing the side scattered light plotted against the forward scattered light for live control cells, dead control cells, and cells incubated with 7 μM peptides Fl-ArgTat, Fl-Auh49Tat, Fl-Auh56Tat and Fl-Auh57Tat. The gate used to restrict the population of cells analyzed is shown and labeled as P …………..98 Figure 3-22. Flow cytometry results showing the side scattered light plotted against the forward scattered light for live control cells, dead control cells, and cells incubated with 120 μM peptides Fl-ArgTat, Fl-Auh49Tat, Fl-Auh56Tat and Fl-Auh57Tat. The gate used to restrict the population of cells analyzed is shown and labeled as P1…………..99 Figure 3-23. Flow cytometry results showing the PI fluorescence against the FITC fluorescence for live control cells, dead control cells, and cells incubated with 7 μM peptides Fl-ArgTat, Fl-ArgTat, Fl-Auh49Tat, Fl-Auh56Tat and Fl-Auh57Tat. The PI threshold used to restrict the population of cells analyzed is shown and labeled as P2..99 Figure 3-24. Flow cytometry results showing the PI fluorescence against the FITC fluorescence for live control cells, dead control cells, and cells incubated with 120 μM peptides Fl-ArgTat, Fl-ArgTat, Fl-Auh49Tat, Fl-Auh56Tat and Fl-Auh57Tat. The PI threshold used to restrict the population of cells analyzed is shown and labeled as P2……………………………………………………………………………………...100 Figure 3-25. Flow cytometry results for cellular uptake into Jurkat cells in the presence of fetal bovine serum upon incubation with (A) 7mM Tat-derived peptides and (B) 120mM Tat-derived peptides for 15 min at 37°C. ........................................................ 100 Figure 3-26. Flow cytometry results showing the fluorescence signal for live control cells, and cells incubated with 7 μM peptides Fl-ArgTat, Fl-Auh49Tat, Fl-Auh56Tat and Fl-Auh57Tat for 15 minutes at 37 oC…………………………………………….101 Figure 3-27. Flow cytometry results showing the fluorescence signal for live control cells, and cells incubated with 120 μM peptides Fl-ArgTat, Fl-Auh49Tat, Fl-Auh56Tat and Fl-Auh57Tat for 15 minutes at 37 oC…………………………….101 List of Tables Table 2-1. Sequences of Peptides Designed to Investigate the Effect of Lysine Acetylation on Helix Stability ......................................................................................... 27 Table 2-2. Sequences of Peptides Designed to Investigate the Effect of Lysine Acetylation on Hairpin Stability ...................................................................................... 28 Table 2-3. Mean Residue Ellipticity at 222 nm and Fraction Helix (fhelix) of AcK or Auh containing peptides .......................................................................................................... 31 Table 2-4. Helix propensity (w), N-Capping Parameter (n), and C-Capping Parameter (c) Derived from Experimental Measured Fraction Helix Values Based on Modified Lifson-Roig Theorya ........................................................................................................ 32 Table 2-5. The energies of helix formationa for AcK and Auh ....................................... 33 Table 2-6. The comparison of 3JHNα for HPTFAcKAla, HPTFAuhAla, HPTAcKAla HPTAuhAla, HPTUAcKAla and HPTUAuhAla, ........................................................... 36 Table 2-7. The statistical survey of the structural data of acetylated lysine sites……....42 Table 2-8. The concentration of peptides in NMR spectroscopy analysis...……...........55 Table 2-9. The 1H Chemical Shift Assignments for Peptide HPTAcKAla. .................... 56 Table 2-10. The 1H Chemical Shift Assignments for Peptide HPTFAcKAla. ................ 57 Table 2-11. The 1H Chemical Shifts Assignments for Peptide HPTUAcKAla. .............. 58 Table 2-12. The 1H Chemical Shift Assignments for Peptide HPTAuhAla. ................... 59 Table 2-13. The 1H Chemical Shift Assignments for Peptide HPTFAuhAla. ................ 60 Table 2-14. The 1H Chemical Shifts Assignments for Peptide HPTUAuhAla. .............. 61 Table 3-1. The sequences of Tat-derived peptides to study TAR RNA binding ............. 83 Table 3-2. The sequences of Tat-derived peptides .......................................................... 84 Table 3-3. The peptide stock concentrations as determined by UV-vis spectroscopy. ... 85 Table 3-4. The Z and P values for comparing the dissociation constants for wild type peptide and Tat-derived pepties in the presence of 10 μg/mL bulk E. coli tRNA. ......... 88 Table 3-5. The Z and P values for comparing the dissociation constants for wild type peptide and Tat-derived peptides in the presence of 10 μg/mL bulk E. coli tRNA. ....... 90 Table 3-6. The mean fluorescence intensity of Tat-derived peptides. ............................. 95 Table 3-7. The percent cellular uptake of Tat-derived peptides. ..................................... 96 Table 3-8. The Z and P value of the mean fluorescence intensity at 7 μM for all peptides in cellular uptake assays. ................................................................................................. 97 Table 3-9. The Z and P value of the mean fluorescence intensity at 120μM for all peptides of cellular uptake assays. ................................................................................... 97 Table 3-10. The mean fluorescence intensity of Tat-derived peptides .......................... 101 Table 3-11. The percent cellular uptake of Tat-derived peptides .................................. 102 Table 3-12. The Z and P value of the mean fluorescence intensity at 7μM for all peptides in cellular uptake assays. ................................................................................. 103 Table 3-13. The Z and P value of the mean fluorescence intensity at 7μM for all peptides in cellular uptake assays. ................................................................................. 103 Table 3-14. Reagents for Preparating the Separating Gel. ............................................ 119 Table 3-15. Reagents for Preparation Different Concentration of Samples. ................. 120 List of Schemes Scheme 2-1. Synthesis of Auh-containing peptides ....................................................... .29 Scheme 3-1. Synthesis of Auh-containing peptides ........................................................ 82 Scheme 3-2. Synthesis of 6-carboxy-fluorescein-containing peptides ............................ 82 | |
| dc.language.iso | en | |
| dc.subject | 細胞穿透胜? | zh_TW |
| dc.subject | 離胺酸 | zh_TW |
| dc.subject | Tat衍生胜? | zh_TW |
| dc.subject | 乙醯化 | zh_TW |
| dc.subject | 辨識核糖核酸 | zh_TW |
| dc.subject | Lysine | en |
| dc.subject | Acetylation | en |
| dc.subject | Tat-derived peptides | en |
| dc.subject | RNA recognition | en |
| dc.subject | Cellular uptake | en |
| dc.title | 乙醯化離胺酸對蛋白質二級結構之穩定性及對核糖核酸辨識與細胞穿透之影響 | zh_TW |
| dc.title | Effect of Lysine Acetylation on Protein Secondary Structure Stability, RNA Recognition, and Cell Penetration | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 黃人則(Jen-Tse Huang),何佳安(Ja-An Ho) | |
| dc.subject.keyword | 乙醯化,離胺酸,Tat衍生胜?,辨識核糖核酸,細胞穿透胜?, | zh_TW |
| dc.subject.keyword | Lysine,Acetylation,Tat-derived peptides,RNA recognition,Cellular uptake, | en |
| dc.relation.page | 124 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-01-15 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| 顯示於系所單位： | 化學系 | |
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