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研究生(外文):Cheng-Chang Chen
論文名稱(外文):Assemblies of ORF8a from SARS-CoV, and BST-2 with Vpu from HIV-1 within the lipid membrane
指導教授(外文):Wolfgang B. Fischer
外文關鍵詞:ion channelmembrane proteinself-assembly
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  在第一部分的論文中,針對人類急性呼吸道症候群冠狀病毒的結構蛋白之一的開放式讀架(open reading frame) 8a膜蛋白進行研究。ORF8a膜蛋白全序列為三十九個胺基酸所排列組成,其中包含一段單一的穿膜區域。本實驗所使用的全序列純膜蛋白由胜固相合成法所製成。實驗中發現,當它在人工合成的雙層脂質膜中重組後會形成一個具有陽離子選擇性的陽離子通道。由膜電位電生理的實驗記錄顯示,ORF8a蛋白在攝氏三十八點五度的環境中可以展現一個主要導電性大約8.5 pS (pico-sieman) 的離子通道活性。在電腦模擬的研究方面,ORF8a蛋白其中的二十二個胺基酸長度的穿膜部分被假設為理想的單體螺旋結構單位,藉由此單體螺旋建立起排列成束的結構模型並將其嵌置於高度水合之POPC雙層脂質細胞膜之中,俾以進一步研究取得更多蛋白結構的資訊。根據電腦模擬的結果指出,ORF8a蛋白有可能是由五個相同的單體螺旋結構單位所聚合的離子通道。

  Many genomes of viruses encode small membrane spanning proteins which are proposed to alter membrane permeability or cell response. These membrane proteins are getting into the focus for antiviral therapy since they are essential for some of the viruses. One of the common themes of the mechanism of function of the proteins is to self-assemble to form the functional form.

  In the first part of this study, the open reading frame (ORF) 8a membrane protein encoded in structural region of Human Severe Acute Respiratory Syndrome Coronavirus is investigated. The full length ORF8a protein is 39 residues long and contains a single transmembrane domain. Full length protein is synthesized using solid phase peptide synthesis. When reconstituted into artificial lipid bilayers it forms cation-selective ion channels. The bilayer recordings show ion channel activity with a main conductance level of around 8.5 pS also at elevated temperatures (38.5°C). In silico studies with a 22 amino acid transmembrane (TM) domain are done to assess conformational space of the monomeric ORF8a helix. With this monomeric helix homooligomeric helical bundle models are built and embedded in a fully hydrated 1-palmitoyl-2-oleoyl-sn-glycerol-3 -phosphatidylcholine bilayer. Results of computational modeling suggest that SARS ORF8a could form a pentameric pore.

  The second part of this study focuses on the evaluation of amino acids within the TM domains (TMDs) of Vpu and BST-2 and their role in the putative assembly process. The human and non-human primates BST-2 TMDs, including the LG-insertion mutant, are compared. Data from flow cytometry assays of Vpu-mediated modulation of BST-2 are presented. The data illustrate that the L29G30 TMD mutant of Rhesus BST-2 is down regulated from the cell surface by Vpu and also expressed at a lower level than other BST2 types. These results imply that an interaction between TMDs of BST-2 and Vpu should exist. We also have started to model the interaction of the TMDs of BST-2 and Vpu mutant (A18H) using computational methods.
Acknowledgment 3
Abstract 5
論文摘要 7
Introduction: 9
Assembly of homooligomers, e.g. SARS-ORF8a 10
Assembly of heteroligomers, e.g. BST-2 and Vpu 12
Materials and methods: 13
ORF8a peptide synthesis 13
Reconstitution and channel recordings of ORF8a 13
Flow Cytometry for BST-2 14
Computational Methods 14
Results: 19
Homooligomeric helices of ORF8a peptide 19
Transmembrane Domain of ORF8a 19
Channel recording of ORF8a 20
MD simulations of ORF8a 25
Heteroligomeric helices of Vpu from HIV-1 with host vector BST-2 32
Transmembrane domains of Vpu and BST-2 32
Vpu mediated downregulation of Human BST-2 and L29G30 insertion mutant non-primate BST-2 33
MD simulation of TMDs of BST-2 and Vpu 37
Assembly of TMDs of BST-2 and Vpu 41
Discussion: 44
Computational results: 44
Interactions of Transmembrane Domains of BST-2 and Vpu 45
Conclusion 46
Reference 48
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