臺灣博碩士論文加值系統

胃潰瘍、十二指腸潰瘍還有胃癌的發生和幽門螺旋桿菌的感染息息相關，而許多先前報導指出，幽門螺旋桿菌所產生的致病因子，與其在腸胃道的感染也扮演著非常重要的角色。在我們之前的研究中，鑑定出了和導致胃癌發生相關的新致病因子GroES (HpGroES)，而此研究中顯示，HpGroES會藉由結合第四型類鐸受體(Toll-like receptor 4, TLR4)這條路徑產生白細胞介素八(interleukin-8, IL-8)。其中，HpGroES上的功能區域B部分，對於結合第四型類鐸受體扮演著很重要的角色。在本篇研究中，我們探討了在HpGroES功能區域B上面的組氨酸 (histidine)，在此機制中扮演的重要性，因此我們分別純化出了各個組氨酸的點突變，結果發現，組氨酸H96, H104, H115突變後，其導致產生白細胞介素八的能力和WT組相同，顯示此三個組氨酸位點對於致發炎反應是不需要的。相對的H100, H102, H108, H113, H118在產生白細胞介素八的這條路徑當中，是扮演重要的角色。進一步研究顯示，H100, H102, H108, H113, H118也參與了在功能區域B上與鎳金屬的結合，而其中的H102, H108, H113, H118參與了維持功能區域B的構型的角色，以利於與四型類鐸受體的結合和白細胞介素八的產生。此外，在分子模擬模型的結果表示H100, H102, H108會和第一個鎳金屬結合，H113和H118則會和第二個鎳金屬結合，結果顯示在功能區域B上的區域序列HDH(X)nH對於結合鎳金屬扮演重要的角色。而進一步的雙突變蛋白實驗結果顯示，H100A/H102A, H100A/H108A, H102A/H108A, H113A/H118A也影響了在功能區域B上與鎳金屬的結合，並影響其構型，降低了蛋白與四型類鐸受體的結合以及白細胞介素八的產生。因此，在本篇研究當中，我們找出了在HpGroES功能區域B上面的H102, H108, H113, H118在維持羧基端構型的完整性，和產生白細胞介素八上扮演著非常重要的角色。

Helicobacter pylori infection is associated with the development of gastric and duodenal ulcers as well as gastric cancer. Many virulence factors of H. pylori also involve in inflammation response or the development of peptic ulcer and gastric cancer when H. pylori colonization at gastrointestinal tract. GroES of H. pylori (HpGroES) was previously identified as a gastric cancer-associated virulence factor. Our group showed that HpGroES induces interleukin-8 (IL-8) cytokine release via a Toll-like receptor 4 (TLR4)-dependent mechanism and domain B of the protein is crucial for interactions with TLR4. In the present study, we investigated the importance of the histidine residues in domain B. To this end, a series of point mutants were expressed in Escherichia coli, and the corresponding proteins purified. Interestingly, H96, H104 and H115 were not essential, whereas H100, H102, H108, H113 and H118 were crucial for IL-8 production and TLR4 interactions in KATO-III cells. These residues were involved in nickel binding. Four of five residues, H102, H108, H113 and H118 induced certain conformation changes in extended domain B structure, which is essential for interactions with TLR4 and consequent IL-8 production. Moreover, the results of molecular modeling indicated that H100, H102 and H108 interacted with one nickel ion, and H113 and H118 interacted with another nickel ion. This indicated the nickel prefer coordinate motif HDH(X)nH on domain B. According to the modeling result, the double mutants H100A/H102A, H100A/H108A, H102A/H108A, H113A/H118A were constructed and purified. These double mutants exhibited greatly reduced IL-8 production, affinity for nickel ion and significantly disappeared and formed a compact oblate shape compared with WT. We conclude that interactions of nickel ions with histidine residues in domain B help to maintain the conformation of the C-terminal region to conserve the integrity of the HpGroES structure and modulate IL-8 release.

口委審定書 i
摘要 ii
Abstract iii
圖目錄 vii
表目錄 ix
Abbreviations x
Chapter I - Overview and Rationale 1
1.1 Microbiology and epidemiology of Helicobacter pylori 2
Table 1-1 Prevalence of H. pylori infection and gastric cancer in Asia 3
1.2 Helicobacter pylori infection and gastric diseases/gastric cancer 4
1.3 Helicobacter pylori infection and the immune responses 8
1.4 Virulence factors of Helicobacter pylori and the immune responses 10
1.5 Specific aim 14
Chapter II - Importance of the C-terminal histidine residues of Helicobacter pylori GroES for Toll-like receptor 4 binding and interleukin-8 cytokine production 15
2.1 Introduction 16
2.2 Materials and Methods 18
2.3 Results 24
2.4 Discussion 30
Chapter III – Conclusion and Perspectives 34
Chapter IV – Tables and Figures 37
Table I. Primer sequences used for HpGroES constructs 38
Table II. The percentage of secondary structure content of WT and histidine mutants calculated by the CDSSTR program 39
Table III. Kd and Bmax values of WT and histidine mutant proteins 40
Table IV. SAXS data analysis of WT and various histidine mutants 41
Figure 1. Schematic representation of the domain structures and domain B sequences (residues 91-118) of WT and histidine mutants. 42
Figure 2. FPLC profiles of purified WT and histidine mutant proteins. 43
Figure 3. Purified His-tagged fusion WT and histidine mutants were separated via 15% SDS-PAGE and stained with Coomassie Blue. 44
Figure 4. The IL-8 levels of WT and histidine mutants by ELISA assay from KATO-III cells. 45
Figure 5. The steady state binding affinity analysis of WT and histidine mutants to immobilized TLR4 by surface plasmon resonance (SPR) assay 46
Figure 6. Visible Circular dichroism (CD) spectra of Ni2+ bound to WT and histidine mutant proteins. 48
Figure 7. Far-ultra violet (UV) circular dichroism (CD) analysis of the differences between histidine mutant and WT proteins. 50
Figure 8. SAXS data analysis and ab initio models of WT and variant proteins. 51
Figure 9. IL-8 levels of WT, H118A and histidine double mutants by ELISA assay from KATO-III cells. 53
Figure 10. Visible Circular dichroism (CD) spectra of Ni2+ bound to WT and various histidine double mutants. 54
Figure 11. The averaged envelopes DAMMIN models of various histidine double mutants. 55
Reference 56
Appendix 71
Supplementary Method 72
Supplementary Figure S1. Binding abilities of WT and histidine mutant proteins to TLR4 on KATO-III cell membranes evaluated via confocal microscopy. 73
Supplementary Figure S2. Surface plasmon resonance (SPR) assay of specific binding affinities of WT and histidine mutants to immobilized TLR4. 75
Supplementary Figure S3. Model of the domain B with putative nickel binding residues 76

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