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研究生:張智培
研究生(外文):Chih-Pei Chang
論文名稱:蛇毒蛋白Rhodostomin與人類血小板Integrins交互作用之探討
論文名稱(外文):Characterization of Interactions Between Rhodostomin and Integrins of Human Platelet
指導教授:羅時成羅時成引用關係
指導教授(外文):Szecheng John Lo
學位類別:博士
校院名稱:國立陽明大學
系所名稱:微生物暨免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:127
中文關鍵詞:蛇毒蛋白血小板整合蛋白去整合蛋白插入突變攫取試驗
外文關鍵詞:snake venomplateletintegrindisintegrininsertion mutagenesispull-down assay
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中 文 摘 要
細胞的吸附作用調控著很多重要的生理功能, 包括胚胎的發育, 細胞的游移, 生長, 分化, 以及免疫細胞的活化, 血小板的凝集, 腫瘤細胞的轉移. Integrins為媒介細胞與細胞以及細胞和細胞外間質交互作用最主要的分子, 其雙向訊息傳導的功能整合了細胞外的訊息以及細胞內的生理狀態. Disintegrin家族為一群由蛇毒中分離出來的蛋白所組成, 其成員在結構上的特性為小型多胜鏈, 富含cysteine以及一段RGD或KGD序列. Disintegrin已被證實能阻斷fibrinogen與血小板上integrin的結合以抑制血小板的凝集. Rhodostomin(又稱為kistrin, 簡稱RHO)是從Agkistrodon rhodostoma(又稱Calloselasma rhodostoma, 馬來亞蝮蛇)蛇毒中所純化出來的disintegrin, 包含68個氨基酸, 12個cysteine, 6對雙硫鍵, 以及RGD motif在氨基酸位置49-51. 關於rhodostomin的生物功能已經有很多的研究報告, 尤其是將rhodostomin的RGD序列換為LDV所造成之rhodostomin-LDV嵌合體具有類似fibronectin之LDV片段的結合活性及專一性. 但是, rhodostomin分子骨架以及RGD鄰近序列對於rhodostomin活性的重要性仍然未明. 本實驗利用插入突變以及取代突變的方式, 探討鄰近序列與RGD相對位置的重要性以及分子骨架所扮演的角色. GST攫取試驗證實RGD的4個N端插入突變以及3個C端插入突變會降低與integrin aIIbb3的結合能力. 但是2個緊接在RGD後面的插入突變[GST-RHO(51+A)以及GST-RHO(52+A)]以及位於Cys57之前的插入突變[GST-RHO(56+A)]則幾乎完全喪失與aIIbb3結合的能力. 此外, 血小板凝集抑制試驗以及血小板吸附試驗的結果都與攫取試驗的結果一致. 但是Pro53的取代突變種只會喪失與母系CHO細胞的吸附能力, 對於表現avb3或是aIIbb3的CHO細胞吸附則是稍微減少. 為了進一步評估rhodostomin分子骨架的功能, 本實驗比較rhodostomin[GST-RHO(RGD)], 人類MDC-15之disintegrin-like區域(GST-D15)以及rhodostomin-D15嵌合體對於integrin aIIbb3的結合能力. GST攫取試驗發現GST-D15對於integrin aIIbb3的結合能力遠低於GST-RHO(RGD), 而與rhodostomin-D15的嵌合體相當. 但是rhodostomin-D15嵌合體可以讓表現aIIbb3的CHO細胞吸附而GST-D15不行. 此外, 帶有Pro取代突變的GST-D15突變種(GST-D15/CP, GST-D15/MP)也可以讓表現aIIbb3的CHO細胞吸附. 總結上述結果, 本實驗提出堅強的證據證實: (1) rhodostomin真正參與integrin結合作用的區域是Arg49-Gly50-Asp51-Met52-Pro53. 除了RGD motif之外, 位於RGD的C端第2個氨基酸Pro53對於integrin的結合也是非常重要; (2) 本實驗第一次比較蛇毒disintegrin與人類MDC在integrin交互作用上的活性差異. 人類MDC之disintegrin-like區域(GST-D15)的integrin結合能力遠低於蛇毒disintegrin[GST-RHO(RGD)], 而其原因為RGD motif的鄰近序列不同所導致; (3) rhodostomin的分子骨架非常適合與fibrinogen的receptor, 即integrin avb3和aIIbb3結合. 同時, 利用人類MDC-15之RGD及其鄰近序列共9個氨基酸所製造之rhodostomin-D15嵌合體, 表現出近似GST-D15之integrin結合活性. 因此, 本實驗證實rhodostomin的分子骨架可以呈現來自其它disintegrin相關分子的9個氨基酸片段.

Abstract
Cell adhesion plays critical roles in directing the embryonic development, cell migration, proliferation, differentiation, as well as activation of immunocytes, aggregation of platelet, and cancer metastasis. Integrins are the major receptors mediated cell-cell and cell-extracellular matrix interactions, the bi-directional signal transducing activity of integrin integrates the extracellular signals and intracellular events. Disintegrins represent a protein family of low molecular weight, cysteine-rich and RGD- or KGD-containing peptides isolated from snake venom. They have been proved to inhibit platelet aggregation by blocking the binding between fibrinogen and platelet integrins. Rhodostomin(also called kistrin, RHO in abbreviation, a member of disintegrin) is derived from snake venom of Agkistrodon rhodostoma(also called Calloselasma rhodostoma, Malayan pit viper), which contains 68 amino acids, including 12 cysteine residues, 6 disulfide bonds, and an RGD motif at positions of 49-51. Intense studies have been done to define the biological functions of rhodostomin. Specifically, the rhodostomin-LDV chimeras which contain LDV motif in the natural RGD site had been proved to exhibit potency and specificity similar to the LDV-containing fragment of fibronectin. However, the role of presenting scaffold and the influence of relative distance between flanking residues and RGD motif of rhodostomin are unclear. In this study, by utilizing insertion mutagenesis and substitution mutagenesis, the importance of distance between RGD and flanking residues and the specific function of presenting scaffold of rhodostomin were characterized. GST pull-down assays indicated the 4 alanine insertions at N-terminal flanking region and 3 alanine insertions at C-terminal flanking region of RGD motif were able to reduce integrin aIIbb3 binding activity to a limited extent. In contrast, 2 insertions[GST-RHO(51+A) and GST-RHO(52+A)] immediately next to RGD and 1 insertion[GST-RHO(56+A)] in front of the Cys57 caused almost complete loss of binding activity to aIIbb3. The results of platelet aggregation assay and platelet adhesion assay for the insertion mutants were consistent with results of pull-down assay. However, Pro53-substituted mutants abolished parental CHO cells adhesion but mild reduced avb3- or aIIbb3-expressing CHO cells adhesion. To further evaluate the presenting function of rhodostomin scaffold, the aIIbb3 binding activity of rhodostomin[GST-RHO(RGD)], disintegrin-like domain of MDC-15(GST-D15) and fragment-graft rhodostomin-D15 chimeras were compared. The results of pull-down assay showed the binding activity of GST-D15 is much weaker than GST-RHO(RGD) and similar to rhodostomin-D15 chimeras. However, rhodostomin-D15 chimeras can mediate aIIbb3-expressing CHO cells adhesion but GST-D15 cannot. Besides, Pro-substituted D15 mutants(GST-D15/CP, GST-D15/MP) also mediate the adhesion of aIIbb3-expressing CHO cells. In summary, this study provides strong evidences that (i) the exact region of rhodostomin involved in integrin-binding interaction is Arg49-Gly50-Asp51-Met52-Pro53. In addition to the RGD motif, the Pro53 at position next 2 to RGD is also important in integrin binding; (ii) the low aIIbb3 binding activity of the disintegrin-like domain of MDC-15 is due to the influence of the flanking sequence of RGD motif; and (iii) the rhodostomin scaffold is optimized for interacting with fibrinogen receptors, integrin aIIbb3 and avb3. In addition, the integrin-binding activity of rhodostomin-D15 chimera is similar to GST-D15. This result indicated the scaffold of rhodostomin is suitable for presentation of large fragment as 9 amino acids from disintegrin-related molecules.

封面
中文摘要
英文摘要
名詞縮寫
1. 緒論
1.1 引言
1.2 細胞吸附作用的生理功能與參與的分子
1.3 Integrin的結構與生理功能
1.4 血小板之凝血機轉
1.5 蛇毒蛋白和disintegrin
1.6 MDC的分子結構及可能的生理功能
1.7 近代針對細胞吸附作用的藥物發展
1.8 本實驗之研究動機與重要性
1.9 本實驗之主要目標
1.10 本實驗之研究策略
2. 材料
2.1 藥品
2.2 實驗套組
2.3 抗體
2.4 酵素
2.5 大腸桿菌株
2.6 細胞株
2.7 質體
2.8 引子(Primers)
3. 方法
3.1 Rhodostomin片段之序列相似性比對
3.2 質體之構築
3.3 大腸桿菌之轉形(Transformation)
3.4 GST融合蛋白之純化
3.5 人類血小板之製備
3.6 SDS-聚丙烯醯電泳(SDS-PAGE)
3.7 西方點墨法(Western blot)
3.8 GST攫取試驗
3.9 血小板凝集試驗
3.10 細胞吸附試驗
4. 結果
4.1 Rhodostomin片段之序列相似性比對
4.2 以插入突變鑑定RGD序列與鄰近氨基酸相對位置之重要性
4.3 以取代突變進一步探討Pro53對於rhodostomin與integrin結合之影響
4.4 人類MDC-15之disintegrin相似區域與integrin結合之能力明顯低於rhodostomin
4.5 以區域置換突變來探討rhodostomin分子骨架之重要性
4.6 利用D15之取代突變種來採討Pro之功能
4.7 總結
5. 討論
5.1 序列相似性比對之分析結果
5.2 GST融合蛋白之生物活性
5.3 Ala插入突變對於rhodostomin生物活性的影響
5.4 Pro53對於rhodostomin生物活性的重要性
5.5 Rhodostomin分子骨架的功能
5.6 MDC-15之disintegrin-like區域可能的生物功能
5.7 Integrin與ligand交互作用的可能機轉
5.8 蛇毒研究之未來展望及臨床應用
6. 參考文獻
7. 圖表
8. 附錄
8.1 發表論文
8.2 CD-ROM光碟權利宣告及使用方式

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