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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 董馨蓮 | |
dc.contributor.author | Yi-Hsiu Fang | en |
dc.contributor.author | 方怡琇 | zh_TW |
dc.date.accessioned | 2021-06-13T00:08:04Z | - |
dc.date.available | 2016-10-07 | |
dc.date.copyright | 2011-10-07 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-08-05 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/28430 | - |
dc.description.abstract | T-cell receptor(TCR)接收抗原刺激後,BCL10與CARMA的CARD-CARD進行結合,此時MALT1因與BCL10結合而能藉助CARMA調控的聚合作用(oligomerization) ,進而吸引TRAF6結合且活化NF-κB以及具有切割蛋白質的能力,顯示聚合作用對MALT1執行功能的重要性。因此我們欲利用人工強迫聚合作用的方法了解其對於MALT1執行功的影響。
在293T細胞中,BCL10可作為促使MALT1進行聚合作用的活化因子。所以我們利用BCL10 truncations定義出可能足以進行聚合作用的CARD moiety,構築出CARD(106)-2Ig-CLD-myc、CARD(101)-2Ig-CLD-myc以及分別在CARD與CLD上進行突變的negative controls:CARD(106)L41R-2Ig-CLD-myc、CARD(106)-2Ig-CLDC464A-myc、CARD(101)L41R-2Ig-CLD-myc以及CARD(101)-2Ig-CLDC464A-myc。 接著利用與已經失去聚合能力卻還保留和MALT1結合區域及被切割位點的BCL10L41R-GFP共同轉染的方法當受質來確認我們構築的重組蛋白是否具有protease活性。結果顯示CARD(106)-2Ig-CLD-myc及CARD(101)-2Ig-CLD-myc的確具有protease活性。而CARD(106)-2Ig-CLDC464A-myc及CARD(101)-2Ig-CLDC464A-myc則因破壞掉CLD所以如預期無法切割受質。利用點突變破壞CARD moiety的CARD(106)L41R-2Ig-CLD-myc及CARD(101)L41R-2Ig-CLD-myc並未完全失活,仍具有些許protease活性,。接著透過共同免疫沉澱以及免疫螢光染色的實驗結果顯示與受質的結合對於受質被paracaspase CLD活性所切割是必要的條件之一。 另外我們也連接能進行雙聚合作用(dimerization)的GyraseB moiety給2Ig-CLD及△2Ig-CLD,構築出GyraseB-2Ig-CLD-myc和GyraseB-△2Ig-CLD-myc。利用Luciferase assay測定出兩者皆有顯著的NF-κB活化,代表GyraseB的連接促使聚合作用的發生。然而分別將BCL10-GFP或BCL10L41R-GFP與GyraseB-2Ig-CLD-myc共同轉染時,卻無法觀察到切割現象。Gyrase B moiety即使能貢獻聚合作用,但可能造成構型不適當的改變而影響受質進入CLD active site,而無觀察到預期的受質切割現象。 根據以上實驗結果,不同的強迫聚合作用可能活化MAL1不同的功能,細節會在本文中進一步的討論。 | zh_TW |
dc.description.abstract | CARMA1-BCL10-MALT1(CBM) complex is central to antigen receptor-triggering NF-κB signaling of lymphocyte activation and thereby controls the expression and secretion of cytokines that are essential for lymphocyte proliferation. Upon activation, BCL10 acting as an upstream adaptor to recruit MALT1 into the context of oligomerized CBM signalsome. Oligomerized MALT1s are able to recruit TRAF6 and subsequently activate NF-κB. Also, oligomerized MALT1 has proteolytic activity.
We are interested in how oligomerization controls the function of MALT1. My aim is to construct a constitutively active paracaspase by enforcing self-oligomerizaiton. BCL10 is an oligomerization activator in 293T cells. I fused N-terminal CARD of BCL10 with CLD (Caspase Like Domain) of MALT1, generating CARD(106)-2Ig-CLD-myc and CARD(101)-2Ig-CLD-myc respectively. Fusion constructs with mutations to abolish the catalytic activity CARD(106)-2Ig-CLDC464A-myc and CARD(101)-2Ig-CLDC464A-myc and mutations to disrupt the CARD function CARD(106)L41R-2Ig-CLD-myc and CARD(101)L41R-2Ig-CLD-myc were also generated to serve as negative controls. BCL10L41R-GFP, losing its oligomerization ability but retaining its ability to interact with MALT1, was utilized as a substrate. Cotransfection of BCL10L41R-GFP with variable fusion constructs was performed to test the proteolytic activity of these recombinant proteases. Both CARD(106)-2Ig-CLD-myc and CARD(101)-2Ig-CLD-myc showed prominant proteolytic activity. Catalytic inactive mutants CARD(106)-2Ig-CLDC464A-myc and CARD(101)-2Ig-CLDC464A-myc lose their ability to cleave BCL10L41R-GFP as expected. CARD(106)L41R-2Ig-CLD-myc and CARD(101) L41R--2Ig-CLD-myc showed less proteolytic activity than their wild type counterpart. Co-immunoprecipitation analysis and immunefluorescence staining assay confirmed that the interaction between the recombinant protease and its substrate was required for CLD-dependent cleavage. ATP-dependent dimerization domain of GyraseB was utilized as an oligomerization moiety in this study. Both GyraseB-2Ig-CLD-myc and GyraseB-△2Ig-CLD-myc were generated and tested. They showed significantly strong NF-κB activation ability as compared to MALT1. However, GyraseB-2Ig-CLD-myc was not able to cleave BCL10L41R-GFP or BCL10-GFP. Fusion constructs with different oligomerization moiety showed apparently distinct properties. The implication will be discussed in the text. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T00:08:04Z (GMT). No. of bitstreams: 1 ntu-100-R98445126-1.pdf: 4800650 bytes, checksum: 60ec4de69c568303c1292ecdd3ff3992 (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | 口試委員會審定書.................................i
致謝....................ii 中文摘要...........iii 英文摘要............v 目錄..................vii 第壹章 緒論......1 一、NF-κB 訊息傳遞.............................1 二、CBM複合體參與活化NF-κB........2 三、BCL10.........5 四、MALT1........7 第貳章 研究目的................................14 第參章 材料與方法............................15 一、抗體來源...15 二、實驗使用之質體 (附表一)及質體構築 (附圖) ..........15 三、製備勝任細胞................................15 四、細菌轉型...16 五、小量質體製備...............................16 六、大量質體製備...............................16 七、細胞培養...17 八、細胞轉染...18 九、蛋白質濃度測定...........................18 十、免疫沉澱法...................................18 十一、SDS-PAGE.................................19 十二、西方墨點分析法........................19 十三、冷光酵素測定............................20 十四、免疫螢光染色、Hoechst染色及螢光觀察....................20 第肆章 結果....22 第伍章 討論....31 第陸章 參考文獻................................38 第柒章 結果圖表................................45 第捌章 附錄圖表................................64 圖表目錄 圖一、以共軛焦顯微鏡觀察MALT1與BCL10-GFP單獨在293T細胞中的分布...45 圖二、以共軛焦顯微鏡觀察當共同轉染MALT1與BCL10-GFP在293T細胞中,兩者有co-localizaiton的現象...........................................................................46 圖三、以共軛焦顯微鏡觀察BCL10-GFP deletion constructs在293T細胞中的分布與構造................................................................................................................47 圖四、絲狀結構與NF-κB活化相關............................................................................48 圖五、BCL10L41R-GFP可作為具有持續性活化能力的paracaspase的受質.............49 圖六、CLD上的cysteine464對於切割現象是重要的...............................................50 圖七、分別將∆N-MALT1、∆2Ig-MALT1-myc與BCL10-GFP共同轉染至293T細胞中,以共軛焦顯微鏡觀察是否有co-localizaiton的現象...........................51 圖八、構築有持續性活化能力的paracaspase............................................................52 圖九、以共軛焦顯微鏡觀察CARD(106)-2Ig-CLD-myc、CARD(106)L41R-2Ig-CLD-myc、CARD(106)-2Ig-CLDC464A-myc、CARD(101)-2Ig-CLD-myc、CARD(101)L41R-2Ig-CLD-myc以及CARD(101)-2Ig-CLDC464A-myc在293T細胞中的分布與構造....................53 圖十、CARD(106)-2Ig-CLD具有protease活性.........................................................54 圖十一、CARD(101)-2Ig-CLD具有protease活性.....................................................55 圖十二、以共軛焦顯微鏡觀察CARD(106)-2Ig-CLD-myc、CARD(106)L41R-2Ig-CLD-myc 、CARD(106)-2Ig-CLDC464A-myc與BG或BLG共同轉染至293T細胞中時的分布與構造........................................56 圖十三、CARD(106)-2Ig-CLD-myc能與BCL10L41R-GFP進行結合........................57 圖十四、第一和第二個 immunoglobulin-like domain與BG或BLG的結合對於切割現象是必須的............................................................................................58 圖十五、連接CARD(1-106)moiety與CLD並不會更加強原本活化NF-κB的能力..................................................................................................................59 圖十六、以共軛焦顯微鏡觀察GyraseB-△2Ig-CLD-myc 和GyraseB-2Ig-CLD-myc在293T細胞中時的分布與構造..................................................................60 圖十七、連接GyraseB moiety可促使聚合作用而引起NF-κB活化.........................61 圖十八、以共軛焦顯微鏡觀察GyraseB-∆2Ig-CLD-myc和GyraseB-2Ig-CLD-myc分別與BG共同轉染至293T細胞中時的分布與構造..............................62 圖十九、連接GyraseB moiety並無法活化CLD protease活性..................................63 表一、使用之表現質體................................................................................................64 附圖一、NF-κB 訊息傳遞: Canonical路徑與non-canonical路徑.........................67 附圖二、CBM複合體參與在不同受體引起的NF-κB 訊息傳遞...........................68 附圖三、T細胞受器接收刺激後引起NF-κB訊息傳遞的機制.................................69 附圖四、與BCL10共同轉染的MALT1具有protease活性……………………..70 附圖五、BLG 10無法活化NF-κB…………………………………………………70 附圖六、以共軛焦顯微鏡觀察API2-MALT在293T細胞中的分布與構造.............71 附圖七、API2 moiety的連接可引起活化NF-κB的能力…………………………71 附圖八、構築質體pCMV6-XL5-CARD(1-106)-2Ig-CLD-myc…………………….73 附圖九、構築質體pCMV6-XL5-CARD(1-106)L41R-2Ig-CLD-myc及 pCMV6-XL5-CARD(1-106)-2Ig-CLDC464A-myc……………..75 附圖十、構築質體pCMV6-XL5-CARD(1-106)-△2Ig-CLD-myc………………….76 附圖十一、構築質體pCMV6-XL5-CARD(1-101)-2Ig-CLD-myc………………….78 附圖十二、構築質體pCMV6-XL5-CARD(1-101)L41R-2Ig-CLD-myc及pCMV6-XL5-CARD(1-101)-2Ig-CLDC464A-myc…………..80 附圖十三、構築質體pCMV6-XL5-GyraseB-GFP…………………………………..81 附圖十四、構築質體pCMV6-XL5-GyraseB-2Ig-CLDC464A-myc及 pCMV6-XL5-GyraseB-2Ig-CLDC464A-myc……………….. 83 | |
dc.language.iso | zh-TW | |
dc.title | 構築有持續性活化能力的MALT1 | zh_TW |
dc.title | Construction of a constitutively active MALT1 | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 李明學,蔡錦華 | |
dc.subject.keyword | CBM複合,oligomerization,paracaspase,NF-κB, | zh_TW |
dc.subject.keyword | CBM complex,paracaspase,oligomerization,NF-κB, | en |
dc.relation.page | 83 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2011-08-05 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 微生物學研究所 | zh_TW |
顯示於系所單位: | 微生物學科所 |
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