臺灣博碩士論文加值系統

化膿性鏈球菌(Streptococcus pyogenes)，又稱A群鏈球菌(Group A Streptococcus, GAS)，是造成人類感染疾病的重要病原菌之一。本篇研究著重於探討源自化膿性鏈球菌的壓力反應調控因子PerR的晶體結構與功能的關係。PerR是屬於Fur家族之一的轉錄抑制因子(Transcriptional repressor)。在過量金屬離子或過氧化氫造成的氧化環境下，PerR會失去抑制轉錄作用的功能，原受PerR抑制的基因便開始表現，並幫助化膿性鏈球菌抵抗氧化壓力(Oxidative stress)而增加存活機率。在本篇研究中，藉基因重組的方法將化膿性鏈球菌的PerR基因表現於大腸桿菌(Escherichia coli)中，並藉親和性膠體層析法純化重組蛋白。定性分析結果顯示，PerR以二聚體(Dimer)的形式存在於溶液中，並具有專一性DNA結合的能力。蛋白質晶體結構顯示，PerR屬於金屬蛋白(Metalloprotein)，每一單體結合兩個鋅離子，並處於不活化的結構形態。近觀兩個金屬離子結合位點：一者結合位是為典型的鋅指結構(Zinc-finger motif)，由四個半胱氨酸(Cysteine)分別為Cys104、Cys107、Cys144及Cys147組成；另一結合位稱為調控位點，由六個氨基酸分別為His4、His6、Asn15、His19、His97及His99所構成。兩結合位中任何一個氨基酸突變都會使DNA結合能力喪失，顯示金屬結合與PerR的DNA結合能力密切相關。我們推論PerR可利用調控位點感知過量金屬離子的存在，結合金屬離子使PerR固定於不活化的結構形態。此外，過氧化氫處理後，PerR的二聚體形態會受到破壞，而失去DNA結合能力。綜合而論，我們發現化膿性鏈球菌調控因子PerR的晶體結構及壓力調控機制不同於其他已知的PerR及其他Fur家族蛋白。本研究顯示化膿性鏈球菌的PerR具有雙重的感知機制，對金屬及過氧化氫的刺激做出適當的基因調控，以有效控制化膿性鏈球菌對氧化壓力的反應。

Streptococcus pyogenes, also known as group A Streptococcus (GAS), is a Gram-positive pathogen, which causes a variety of human diseases. In this study, the crystal structure of a stress response regulator, PerR, from GAS has been determined. PerR is a repressor to block transcription initiation by binding to promoter region. In GAS, metals and hydrogen peroxide stresses abolish the DNA-binding ability of PerR. Recombinant GAS PerR protein can be successfully expressed in Escherichia coli and purified by Ni2+-NTA affinity chromatography. GAS PerR is characterized to a dimeric protein which displays the ability to bind dpr promoter DNA containing a consensus sequence, Per box. However, the crystal structure shows that the GAS PerR is a metalloprotein and is captured in an inactive conformation containing two zinc ions per monomer. One of the zinc is located at the conserved zinc-finger motif which is composed by Cys104, Cys107, Cys144, and Cys147; the other zinc coordinates in a pseudo octahedral geometry composed by six residues including His4, His6, Asn15, His19, His97, and His99. Both sites of the zinc coordination are critical for PerR biological function. Mutations at any residues involving in metal-binding sites lead to abolish the DNA-binding ability. Zinc binds to regulatory site and locks the conformation of GAS PerR in inactive form. Hydrogen peroxide also causes the dissociation of PerR from dimer to monomer. To summarize, in this study we have solved the crystal structure of PerR and discovered that the regulation of DNA-binding activity of GAS PerR are different from other homologous PerR and Fur family proteins. We propose that GAS PerR possesses dual sensing mechanisms to respond to metal ion and hydrogen peroxide stresses and regulate oxidative stress response.

中文摘要 I
ABSTRACT III
謝誌 V
CONTENTS VI
TABLE LIST VIII
FIGURE LIST IX
ABBREVIATION XII
CHAPTER 1. INTRODUCTION 1
1.1 Streptococcus pyogenes 1
1.1.1 Genomic features of Streptococcus pyogenes 1
1.1.2 Transmission, infection, and diseases 2
1.1.3 Pathogenesis of severe diseases 2
1.1.4 Treatment of GAS-caused diseases 4
1.1.5 Antibiotics resistance 5
1.2 Oxidative stresses for bacteria 6
1.3 Defense mechanisms for oxidative stress in bacteria 7
1.3.1 Antioxidant enzymes 7
1.3.2 Iron storage and detoxification 8
1.3.3 Others antioxidant molecules and systems 9
1.4 Regulation of oxidative stress response 9
1.4.1 Superoxide sensor proteins: SoxR and SoxS 10
1.4.2 Peroxide-sensing transcription factor: OxyR 11
1.4.3 Organic hydroperoxide resistance regulator protein: OhrR 11
1.4.4 Peroxide response regulator: PerR 12
1.5 The aim of this study 14
CHAPTER 2. EXPERIMENTAL PROCEDURES 16
2.1 Materials 16
2.1.1 Bacterial strains 16
2.1.2 Plasmid 16
2.1.3 Primers 17
2.1.4 Chemicals and other material 17
2.2 Methods 19
2.2.1 Construction of S. pyogenes perR and perR mutant plasmids 19
2.2.2 Transformation of plasmid to E. coli strain 20
2.2.3 Overexpression of PerR and PerR mutant in E. coli and preparation of crude extracts 20
2.2.4 Purification of PerR and PerR mutants 21
2.2.5 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and size-exclusion chromatography 21
2.2.6 Analysis of metal contents of GAS PerR by inductively coupled plasma optical emission spectrometry (ICP-OES) 23
2.2.7 Electrophoretic mobility shift assay (EMSA) for the DNA-binding activity of PerR 24
2.2.7.1 Preparation of dpr promoter DNA 24
2.2.7.2 DNA binding reaction and EMSA 24
2.2.8 Protein crystallization 25
2.2.8.1 Methods of crystallization 26
2.2.8.2 Crystallization of wild-type PerR 26
2.2.9 X-ray data collection and process 27
2.2.10 Structure determination and refinement 28
2.2.10.1 Model building and refinement 29
CHAPTER 3. RESULTS 30
3.1 Sequence alignment of homologous PerR proteins 30
3.2 Purification and characterization of S. pyogenes PerR 30
3.3 The DNA-binding activity of PerR 31
3.4 Crystallographic data and structure determination 31
3.5 Overall structure of PerR 32
3.6 Structures of the Zn-coordinated regulatory site and Zn-finger motif 33
3.7 Effects of hydrogen peroxide treatment 34
CHAPTER 4. DISCUSSION 35
CHAPTER 5. CONCLUSION 39
CHAPTER 6. REFERENCES 40

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