日本腦炎病毒前膜蛋白與套膜蛋白形成異質雙體複合物及重組類病毒顆粒之研究

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研究生：	林應如 Ying-Ju Lin
論文名稱：	日本腦炎病毒前膜蛋白與套膜蛋白形成異質雙體複合物及重組類病毒顆粒之研究 Molecular Characterization of prM and E Proteins Involved in prM-E Heterodimeric Complex Interaction and Recombinant Subviral Particle Formation of Japanese Encephalitis Virus
指導教授：	吳夙欽 Suh-Chin Wu
口試委員:
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生命科學系 Department of Life Sciences
論文出版年：	2005
畢業學年度：	93
語文別：	英文
論文頁數：	123
中文關鍵詞：	日本腦炎病毒
外文關鍵詞：	JEV
相關次數：	點閱：1 下載：0
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黃質病毒的前膜蛋白與套膜蛋白形成的複合物對於未成熟病毒顆粒生合成是很重要的步驟，接著未成熟病毒顆粒經由前膜蛋白切割成膜蛋白的步驟後產生成熟的病毒顆粒並釋放出來。本篇論文利用桿狀病毒表現系統、免疫沉澱法與蔗糖梯度沉降離心分析探討細胞內的日本腦炎病毒前膜蛋白與套膜蛋白複合物的形成。研究一系列C端截短的前膜蛋白與套膜蛋白的交互作用顯示去除前膜蛋白上的穿膜區域後，使得前膜蛋白與套膜蛋白形成的複合物有減少的驅勢。另外利用alanine取代法分析前膜蛋白第93-103個胺基酸區域的結果顯示第99個胺基酸histidine對於前膜蛋白與套膜蛋白複合物的形成有重要的影響。進一步以pulse chase labeling和共軛焦顯微鏡研究發現第99個胺基酸突變的影響並不是因為蛋白質減少或者改變了蛋白質駐足的位置。利用桿狀病毒共同表現前膜蛋白與套膜蛋白可在細胞培養液測到重組類病毒顆粒，然而在第99個胺基酸突變蛋白質中並沒有測得。經黃質病毒屬胺基酸序列分析得知前膜蛋白第99個胺基酸為高度保留性。我們進一步利用刪除, alanine插入和glycine取代法分析前膜蛋白的過膜區域顯示第一個過膜區域，特別是GXXXG motif影響前膜蛋白與套膜蛋白複合物形成和病毒顆粒的形成與釋放。此外，我們也利用alanine插入和取代法分析套膜蛋白的過膜區域，其結果也顯示第一個過膜區域，特別是靠近連接點的區域影響異質雙體複合物和病毒顆粒的形成與釋放。此結果是首次發現前膜蛋白的過膜區域與第99個胺基酸和套膜蛋白的過膜區域對於異質雙體複合物和病毒顆粒的形成是最少需要的區域。這些結果提供前膜與套膜蛋白分子構造對於複合物的形成和病毒顆粒組成機制提供可能的結構和功能的資訊。

Abstract
The formation of flavivirus prM-E complex is an important step for the biogenesis of immature virions, followed by a subsequent cleavage of prM to M protein through cellular protease to result in the production and release of mature virions. The intracellular formations of the prM-E complexes of Japanese encephalitis virus (JEV) were investigated by baculovirus co-expression of prM and E in trans and prM and E in cis in Sf9 insect cells analyzed by anti-E antibody immunoprecipitation and sucrose gradient sedimentation analysis. A series of the carboxyl-terminally truncated prM mutant baculoviruses were constructed to demonstrate that the truncations of the transmembrane (TM) region resulted in a reduction of the formation of the stable prM-E complex. Alanine scanning site-directed mutagenesis on the prM99-103 region indicated that the His99 residue was the critical prM-binding element for the prM-E heterodimeric stable complex formation. The single amino acid mutation at the His-99 residue of prM abolishing the prM-E interaction was not due to the reduced expression or different subcellular location of the mutant prM protein involved in prM-E interactions as characterized by pulse chase labeling and confocal scanning microscopic analysis. Recombinant subviral particles were detected in the Sf9 cell culture supernatants by baculovirus co-expression of prM and E proteins but not by the prM-H99A mutant. Sequence alignment analysis was further conducted in different groups of flaviviruses to show the prM-H99 residues are generally conserved. The TM regions of prM protein on prM-E heterodimeric complex formation and recombinant subviral particles formation of JEV were further characterized and the TM1 region of prM, especially the specific amino acid sequence-GXXXG motif, was demonstrated using deletion, alanine insertion and glycine substitution mutagenesis. The GXXXG motif located in the TM1 region of prM of JEV were identified for the influence of heterodimerization and virus assembly. Furthermore, the TM regions of E protein on prM-E heterodimeric complex formation and recombinant subviral particles formation of JEV were characterized and the TM1 regions and the conserved charged residues (RDR) of the connecting segment of E were demonstrated using alanine insertion and replacement mutagenesis. These data indicate that the TM regions and His99 of prM and the TM regions and the conserved charged residues (RDR) of the connecting segment of E proteins play a crucial role of the biogenesis of JEV envelope. This information, concerning a molecular framework for the prM and E proteins, is considered to elucidate the structure/function relationship of the prM-E complex synthesis and provide the proper trajectory for flavivirus assembly and maturation.

中文摘要………………………………………………………………...I
Abstract………………………………………………………………....II
Acknowledgments…………………………………………………..….IV
Abbreviations………………………………………………………...…V
Contents……………………………..……………………………...…VII
Chapter 1 Research background, Incentive and Aims..........................1
1. Japanese encephalitis virus……………………………………………………….1
1-1. Importance, history, and the transmission cycle……………………………...1
1-2. Genome structure and molecular epidemiology of JE disease……………….3
1-3. Virion and flavivirus life cycle……………………………………………….4
2. Flavivirus  particles………………………………………………………………5
2-1. The structure of flavivirus particles (containing nucleocapsid)……………....5
2-2. The structure of flavivirus subviral particles (no containing nucleocapsid)….7
3. Studies on prM and E proteins of flavivirus…………………………………...10
3-1. Structure and function of prM protein………………………………………10
3-2. Structure and function of E protein………………………………………….12
4. Role of transmembrane regions of membrane proteins of enveloped viruses..13
4-1. membrane anchor and signal sequence……………………………………...13
4-2. Membrane fusion……………………………………………………………14
4-3. Subviral particles formation…………………………………………………15
 5. Research Incentive and Aims…………………………………………………..16
5-1. Identification of prM minimal binding sites for prM-E heterodimerization and subviral particles formation………………………………………...……...16
5-2. Fine mapping of the transmembrane regions of prM and E proteins for prM-E heterodimerization and recombinant subviral particles formation…...……17
Chapter 2 Histidine at Residue 99 and the Transmembrane Region of the Precursor Membrane prM Protein are important for the prM-E heterodimeric Complex Formation of Japanese Encephalitis Virus
2-1. Introduction…………………………………...……………….…………….18
2-2. Materials and methods………………………………………………………20
2-3. Results and discussion………..……………………………………………..27
2-4. Conclusion…………..………..……………………………………………..37
Chapter 3 prM-E Heterodimerization and Recombinant Subviral Particle Secretion Affected by Two Transmembrane Regions and One Connecting Segment in the prM and E Proteins of Japanese Encephalitis Virus
3-1. Introduction………………………………...………………………………..39
3-2. Materials and methods……………………………...……………………….43
3-3. Results and discussion…………………………………...………………….47
3-4. Conclusion……...…………………………..………………….……………61
References………………………………………………………………63
Tables…………………………………………………………………...76 Figures…………………..……………………………………………...79







TABLES LIST
Table 1. Amino acid sequence alignment analysis of the M protein (prM93-167) from the genus Flavivirus…………………………………………………………….76
Table 2. Amino acid sequence alignment analysis of the TM regions of prM protein (prM130-167) from the genus Flavivirus………………………………………77
Table 3. Amino acid sequence alignment analysis of the TM regions of E protein (prM461-500) from the genus Flavivirus……………………………………….78


















FIGURES LIST
Figure 1. The Global Distribution of Medically Important Members of the Japanese Encephalitis Serological group of Flaviviruses…………………………………79
Figure 2. The transmission cycles mosquito-borne viruses………………………….80
Figure 3. The genome structure of JEV……………………………………………...81
Figure 4. Mature virion and immature virion inner structure………………………..82
Figure 5. Flavivirus life cycle………………………………………………………..83
Figure 6. Proposed rearrangement of the E proteins during maturation and fusion…84
Figure 7. Immature flavivirus particles……………………………………………....85
Figure 8. Diagrams of the flavivirus M and E protein ectodomain and transmembrane domain, side view……………………………………………………………….86
Figure 9A. Bac-prME, Bac-E and Bac-prM represent three recombinant baculoviruses encoding prME, E and prM of JEV………………..……………………………87
Figure 9B. Sf9 cells were infected with Bac-prME, Bac-E, co-infected with Bac-prM and Bac-E, infected with JEV in C6/36 and Sf9 cells…………………………..88
Figure 9C. The virus replication kinetics of JEV Ch2195LA strain in C6/36 and Sf9 cells…...…………………………………………………………………………89
Figure 9D. Cross-linking analysis……………………………..………………...…...90
Figure 10A. Mapping the prM binding elements in Sf9 cells co-infected with Bac-E and Bac-prM mutants………………………………………………………..…91
Figure 10B. Sf9 cells were co-infected with Bac-E and Bac-prM mutants……….…92
Figure 10C. The percentage of the prM binding intensity to the prM-E complex in each truncated mutants was determined by phosphorimaging……………....…93
Figure 11. Sucrose gradient sedimentation analysis to determine the prM binding affinity for the prM-E heterodimeric stable complex……………………..……94
Figure 12. Alanine scanning site-directed mutagenesis of the prM99-103 region by constructing Bac-prM-H99A, Bac-prM-G100A, Bac-prM-E101A, Bac-prM-S102A, Bac-prM-S103A……………………………………….……96
Figure 13. Sucrose gradient sedimentation analysis of the five prM mutant proteins for the formation of the prM-E heterodimeric stable complex………………...98
Figure 14. Pulse-chase analysis for the stable formation of prM-E heterodimeric complex.…………………………………………………………….….………99
Figure 15. Colocalization of prM protein with an ER-specific dye, DiIC16(3)……100
Figure 16. Transmission electron micrographs of virus particles stained with uranyl acetate……………………………………………………………………….…101
Figure 17. Illustration of the two transmembrane regions of prM protein……….…102
Figure 18. Characterization of the TM regions of prM protein by the truncation mutagenesis………………………………………………………………..…..103
Figure 19. The transmembrane region truncation mutagenesis of the prM protein for prM-E heterodimerization……………………………………………………..104
Figure 20. Sucrose gradient sedimentation analysis of PEG-precipitated cleared supernatants from Sf9 cells infected with JEV or co-infected Sf9 cells with Bac-prM and Bac-prM truncated mutants……………………………………………..………………...………..105
Figure 21. Characterization of the TM regions of prM protein by alanine insertion mutagenesis………………………………….…………………………….…..106
Figure 22. Alanine insertion mutagenesis of the TM regions of prM protein for prM-E heterodimerization…………………………………………………..….……..107
Figure 23. Sucrose gradient sedimentation analysis of PEG-precipitated cleared supernatants from co-infected Sf9 cells with Bac-prM and Bac-prM insertion mutants……………………………………………..…………..……………..109

Figure 24. Characterization of the GXXXG motif of TM1 region of prM protein by glycine substitution mutagenesis……………………………………………………..…...….……..110
Figure 25. Glycine substitution mutagenesis of the GXXXG motif of TM1 region of prM protein for prM-E heterodimerization………….……………………………………..…….……..111
Figure 26. Sucrose gradient sedimentation analysis of PEG-precipitated cleared supernatants from co-infected Sf9 cells with Bac-prM and Bac-prM glycine substitution mutants…...……………………………………………………..……………..113
Figure 27. Characterization of the connecting segment between TM1 and TM2 of prM protein by alanine replacement mutagenesis.….………………………………..………………..……………..114
Figure 28. Alanine replacement mutagenesis of the connecting segment between TM1 and TM2 of prM protein for prM-E heterodimerization.….…………………………………………..……………..115
Figure 29. Sucrose gradient sedimentation analysis of PEG-precipitated cleared supernatants from co-infected Sf9 cells with Bac-prM and Bac-prM R152A mutant………………….………………………………………..……………..116
Figure 30. Characterization of the TM regions of E protein by alanine insertion mutagenesis………………………………….…………………………….…..117
Figure 31. Alanine insertion mutagenesis of the TM regions of E for prM-E heterodimerization…………………………………………………..….……..118
Figure 32. Sucrose gradient sedimentation analysis of PEG-precipitated cleared supernatants from infected Sf9 cells with Bac-prME and Bac-prME insertion mutants…………..………………………………………………..…………...120
Figure 33. Characterization of the connecting segment between TM1 and TM2 of E protein by alanine replacement mutagenesis……………...…………………….………………………………121
Figure 34. Alanine replacement mutagenesis of the connecting segment between TM1 and TM2 of prM protein for prM-E heterodimerization….………………………….………………………………122
Figure 35. Sucrose gradient sedimentation analysis of PEG-precipitated cleared supernatants from infected Sf9 cells with Bac-prME and Bac-prME replacement mutants.………………………………………………………….…………….123

                                

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