臺灣博碩士論文加值系統

電噴灑游離質譜法結合氫氘交換(HDXMS)已廣泛應用於蛋白質動力學、蛋白質與配位體相互作用結構變化研究。人體血漿中的Beta 2 Glycoprotein I (β2GPI)為載脂蛋白(Apolipoproteins)的一種，它被認為與自體免疫疾病中的一種抗磷脂症候群有密切的關聯，血漿中β2GPI通常維持著環狀的結構，並不會與anti-β2GPI抗體結合，在β2GPI與細胞膜作用改變構相之後，抗體就能與β2GPI結合形成複合體，誘導下游的反應發生。文獻指出β2GPI在與細胞膜作用時會透過表面富含正電荷的domain V和磷脂質帶有負電的親水端結合。
在此我們製備了1,2-dioleoyl-sn-glycero-3-phospho-L-serine(18:1DOPS) 及 Cardiolipin(CL)兩種不同磷脂質組成的vesicle來模擬陰電性脂質膜。藉由氫氘交換質譜分析法研究β2GPI和陰電性脂質膜交互作用情形。結果發現在β2GPI與DOPS脂質膜作用10分鐘後，序列21-27的氫氘交換量明顯上升，表示與DOPS作用之後，domain I和domain V的作用力會下降但不會使環狀張開，僅造成序列21-27突出於環狀結構外；而序列1-20、53-77、175-188、259-268及294-306都有些微下降，由於DOPS的親水端同時含有羧基及胺基，易與蛋白質外部形成靜電作用力及氫鍵作用力造成非專一性吸附。在β2GPI與CL脂質膜作用10分鐘後，序列21-27氫氘交換量有明顯上升的情形，與DOPS作用相似，推測負電價頭端易對此序列造成擾動，為開環之前置行為。當β2GPI與CL脂質膜作用30分鐘之後，序列1-20、21-27、41-51、70-86、153-162、191-198、196-205、273-279、297-306及310-316交換量都有顯著增加，序列1-20、21-27、41-51、297-306及310-316交換量上升表示domain I和domain V之間失去交互作用力使這些區塊暴露，序列70-86、153-162、191-198、196-205及273-279的交換量上升代表環狀打開，包在環中的區塊裸露出來。綜上所述，β2GPI和脂質膜短時間作用會導致domain I和domain V作用力下降，使得序列21-27突出，但仍會保持環狀結構；當β2GPI已與脂質膜表面做良好作用後，環狀會趨向完全張開成鏈狀。

Hydrogen/deuterium exchange (HDX) coupled with mass spectrometry (ESI-MS) has been widely used to study the mechanisms of protein dynamics, domain structure, protein-ligand interactions and protein conformational changes. Beta 2 Glycoprotein I (β2GPI) is a membrane protein and it was discovered to be the major antigen for the antiphospholipid antibodies(aPL Abs) in the antiphospholipid syndrome. The β2GPI complex binds with antibody will interact with some receptors, such as annexin A2, TLR family, glycoprotein Ibα, LRP8 to induce inflammation and prothrombotic. Many studies have suggested that β2GPI is not recognized by aPL Abs in the blood circulation. When negatively charged protein surface become exposed, the domain V of β2GPI will bind to the surface and change conformation. Then the aPL Abs are able to recognize the epitope in domain I of β2GPI.
Here, we prepared 1,2-dioleoyl-sn-glycero-3-phospho-L-serine(18:1DOPS) and cardiolipin (CL) vesicles to simulate anion surface membrane. The interactions of the β2GPI with the anion membrane vesicles were analyzed by hydrogen/deuterium exchange mass spectrometry (HDXMS). The exchange level of sequence 21-27 significantly increased after β2GPI interacted with DOPS for 10 min. This results indicated that the interaction between domain I and domain V decreased, which caused the sequence 21-27 protruding out of the circular shape of the protein structure. β2GPI still maintained the circular conformation while interacting with DOPS. The exchange levels of the highly accessible sequences 1-20, 53-77, 175-188, 259-268 and 294-306 slightly decreased due to the nonspecific adsorption between β2GPI and DOPS by electrostatic force and hydrogen bonds. After β2GPI interacted with CL 10 mins. The exchange amount of sequence 21-27 significantly increased. This result was same with DOPS, suggesting the perturbation of sequence 21-27 is a preliminary behavior caused by the phospholipid binding. After β2GPI interacted with CL for 30 min, the exchange levels in several sequences significantly increased, including 1-20, 21-27, 41-51, 70-86, 153-162, 191-198, 196-205, 273-279, 297-306 and 310-316.The increasing of 1-20, 21-27, 41-51, 297-306 and 310-316 indicated that domain I did not interact with domain V and these sequences have been exposed. The increasing deuteration levels in 70-86, 153-162, 191-198, 196-205 and 273-279 indicated β2GPI conformation changed from ring conformation to chain conformation, leading to the exposure of the inner region. Overall, β2GPI could not change the ring conformation while initial contact with lipid membrane, but sequence 21-27 will be exposed. β2GPI continued to drastically change its conformation from ring to chain conformation while staying on the lipid membrane surface.

目錄
目錄 I
圖表目錄 III
摘要 IV
Abstract V
第一章、 緒論 1
1.1氫氘交換質譜分析法(HXMS) 1
1.2 Beta 2-glycoprotein I 5
1.2.1 Beta 2-glycoprotein I 5
1.2.2 抗磷脂症候群 6
1.2.3 β2GPI抗原表位 6
1.2.4 β2GPI結構 7
1.2.5 氧化壓力影響β2GPI 9
1.2.6 β2GPI構相變化 10
1.3 Tafazzin 10
1.3.1 心磷脂 10
1.3.2 Tafazzin 13
1.3.3 Tafazzin結構 14
1.3.4 Tafazzin相關疾病巴氏症 16
第二章、 掃描式氫氘交換質譜分析法研究β2GPI與脂質膜交互作用情形 17
2.1方法 17
2.1.1材料 17
2.1.2 β2GPI胜肽片段序列確認 18
2.1.3 β2GPI X!Tandem軟體計算與應用 20
2.1.4 β2GPI HDXMS 計算 21
2.1.5 磷脂質微胞製備 22
2.1.6 β2GPI與微胞交互作用 22
2.1.7 β2GPI氫氘交換實驗步驟 22
2.2結果與討論 24
2.2.1 β2GPI胜肽片段 24
2.2.2 β2GPI氫氘交換結果 25
2.2.3 β2GPI與脂質膜作用氫氘交換 27
2.2.3.1 β2GPI與DOPS作用 27
2.2.3.2 β2GPI與Cardiolipin作用 30
2.3結論 35
第三章、 利用氫氘交換質譜分析法研究Tafazzin與脂質膜交互作用情形 38
3.1方法 38
3.1.1材料 38
3.1.2重組大腸桿菌 pET-28a載體 38
3.1.3大腸桿菌系統表達Tafazzin 38
3.1.4純化大腸桿菌系統Tafazzin蛋白質 39
3.1.5純化大腸桿菌系統Tafazzin包涵體蛋白質 40
3.1.6 Tafazzin包涵體蛋白質再折疊(refolding) 40
3.1.7大腸桿菌系統Tafazzin蛋白質活性測試 41
3.2結果與討論 42
3.2.1 Tafazzin蛋白質表達純化 42
3.2.2 大腸桿菌系統Tafazzin包涵體蛋白質 42
3.3 結論 43
參考文獻 44








圖表目錄
圖 一、胜肽片段三種不同交換速率的氫原子 3
圖 二、同一胜肽片段氫氘交換後平均質量位移 4
圖 三、氫氘交換時間與氘化程度關係圖 4
圖 四、β2GPI X-ray晶體結構 8
圖 五、β2GPI雙硫鍵位置分布 8
圖 六、β2GPI表面電荷分布 9
圖 七、心磷脂結構圖 13
圖 八、心磷脂重塑機制 13
圖 九、Tafazzin模擬結構圖 16
圖 一〇、β2GPI序列片段HPLC-ESI-MS色層分析圖 19
圖 十一、氫氘交換質譜分析法實驗步驟(ESI-MS) 23
圖 十二、胃蛋白酶水解β2GPI序列片段圖 24
圖 一三、β2GPI各序列片段氫氘交換含量 26
圖 一四、β2GPI各序列片段氫氘交換含量套入3D結構圖 27
圖 一五、β2GPI與DOPS作用各序列片段氫氘交換含量 28
圖 一六、β2GPI與DOPS反應10分鐘氫氘交換量差異圖 30
圖 一七、β2GPI與CL作用各序列片段氫氘交換含量 31
圖 一八、β2GPI與CL反應10分鐘氫氘交換量差異圖 33
圖 一九、β2GPI與CL反應30分鐘氫氘交換量差異圖 35
圖 二〇、β2GPI與DOPS脂質膜以及CL脂質膜反應後的構形變化模擬圖 37
圖 二十一、Taffzzin NTA-beads純化SDS-PAGE 42
圖 二十二、Taffzzin inclusion body SDS-PAGE 43

表 一、質譜儀參數設定表 20
表 二、DataAnalysis軟體設定條件表 21
表 三、X!Tandem軟體設定條件表 21

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