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系統識別號 U0026-2308201315431200
論文名稱(中文) 探討癌症轉移相關蛋白S100A4的生物物理特性
論文名稱(英文) Biophysical characterization of the cancer metastasis-related protein S100A4
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 101
學期 2
出版年 102
研究生(中文) 謝欣倍
研究生(英文) Hsin-Pei Hsieh
學號 s46004014
學位類別 碩士
語文別 中文
論文頁數 70頁
口試委員 口試委員-羅正汎
口試委員-羅玉枝
指導教授-王淑鶯
中文關鍵字 S100A4  癌症轉移  X光小角度散射 
英文關鍵字 S100A4  cancer metastasis  small-angle X-ray scattering 
學科別分類
中文摘要 S100A4是一個鈣離子結合蛋白質,在分類上屬於S100蛋白質家族,根據過去文獻已得知S100A4參與了癌症腫瘤細胞的轉移。在癌症轉移病人中可以觀察到S100A4蛋白質表現量的上升,因此S100A4蛋白質的表現量與腫瘤細胞的轉移的過是有直接的關聯,至今, S100A4蛋白質表現量也成為臨床上判斷腫瘤轉移的一項重要的指標。S100A4主要是利用兩端(N端和C端)的EF-hand motifs與鈣離子結合。當S100A4與鈣離子結合後會在C端的EF-hand motifs產生顯著的構形上的改變,而這個構形上的改變對S100A4和其他目標蛋白結合來說是重要的。過去研究中指出,將C端鈣離子結合位置進行突變(CM,N65I 和 D67A)或者是將C端的環狀區域的15個胺基酸進行剔除(ΔS100A4)後S100A4與鈣離子結合能力下降,並在小鼠的乳腺細胞中觀察到細胞進行移動和侵襲的能力降低,並顯著的降低了S100A4與目標蛋白質之間結合,因此更進一步的降低了轉移的能力。相反的,上述這些細胞現象在進行N端鈣離子結合位置進行突變(NM,E23A 和D25A)的S100A4的蛋白質中並沒有觀察到。根據這些研究資料我們假設了S100A4蛋白質中將C端區域進行突變之後造成蛋白質結構上的變化因此使得S100A4蛋白質失去原有的生物性功能。故本篇研究主要藉由比較S100A4蛋白質野生株和C端突變株在溶液中的整體構形進而去解釋S100A4蛋白質結構與功能之間的關係。我們首先將3個突變株(NM、CM和 ΔS100A4)重新構築在表現載體上,接著利用親和性鎳離子螯合樹脂色層分析和分子篩選層析法進行蛋白質的純化。從分子篩選層析法實驗中所得到分析結果得知NM和CM均為二聚體的形態存在於溶液之中,但ΔS100A4則以單聚體的形式存在。除此之外,利用圓二色光譜與感應耦合電漿質譜分析儀測試了蛋白質二級結構組成和與鈣離子的結合能力,根據圓二色光譜分析結果指出與其他突變株蛋白相比ΔS100A4具有不同的二級結構組成;另外藉由X光小角度散射技術比較NM和CM在溶液中的構形後得知NM在溶液中的構形和S100A4蛋白質野生株活性狀態的晶體結構是相似的。總結本篇研究得知,S100A4的C端區域對於維持S100A4的結構和功能性來說是相當重要的。
英文摘要 S100A4 is a member of the S100 family of calcium-binding proteins and is involved in tumor metastasis. Elevated S100A4 protein expression is associated with metastatic tumor progression, and is a molecular marker for clinical prognosis. S100A4 binds to calcium through N- and C-terminal EF-hand motifs. S100A4 undergoes a significant conformational change in C-terminal EF-hand motifs when calcium binds. This calcium-dependent conformational change is necessary for S100A4 to interact with its target proteins. Mutation of the C-terminal calcium binding sites on EF hand motif (CM, N65I and D67A) or deletion of the last 15 amino acids of S100A4 C-terminus (ΔS100A4) decreases calcium binding ability, motility/invasion of rat mammary cell line in vitro, and abolishes the interaction with it molecular target. Consequently, these mutants result in the reduction of metastasis. In contrast, these observations were not found on N-terminal EF hand motif mutants (NM, E23A and D25A). We hypothesize that mutation of C-terminal residues results in protein conformational change and leads to loss of function. Therefore, we aim to compare the overall structural conformation of the S100A4 mutants with wild-type protein, and to reveal the structural change and structure-functional relationship of S100A4. Three mutants (NM, CM, and ΔS100A4) were constructed and expressed in E. coli. The recombinant proteins were purified by immobilized affinity chromatography (IMAC) and purity was further polished by size exclusion chromatography (SEC). The wild-type, NM, and CM are dimeric proteins, but the ΔS100A4 is a monomer from SEC profile analysis. We also compared the secondary structure and calcium binding ability of all mutants by circular dichroism (CD) and inductively coupled plasma mass spectrometry (ICP-MS). The results of CD indicate that ∆S100A4 has different secondary structure composition. Small-angle X-ray scattering (SAXS) studies reveal that NM has similar solution conformation to calcium-bound wild-type protein. In summary, the C-terminal region of S100A4 protein has an important role in maintain the protein functions and structure.
論文目次 中文摘要 I
ABSTRACT III
誌謝 V
目錄 VII
圖目錄 X
表目錄 XI
符號及縮寫 XII
第一章 緒論 1
1.1 S100A4的介紹 1
1.1.1 S100A4的蛋白質結構 1
1.1.2 S100A4與癌症的關係 2
1.1.3 S100A4的C端區域對於誘發癌症轉移是重要的 3
1.2 S100蛋白質家族簡介 4
1.3 EF-HAND MOTIF 6
1.4 研究目的 6
第二章 材料與方法 7
2.1實驗材料 7
2.1.1 質體來源 7
2.1.2 實驗藥品及溶液配方 7
2.1.3 實驗菌種培養及保存 7
2.2 實驗方法 8
2.2.1 重組蛋白質質體之建構 (Construction of recombinant protein plasmids) 8
2.2.1.1 商業化套件萃取質體DNA 8
2.2.1.2 傳統法萃取質體DNA (Homemade plasmid extraction) 8
2.2.1.3 聚合酶連鎖反應 (Polymerase chain reaction, PCR) 9
2.2.1.4 限制酶酵素切割及DNA接合反應 (Restriction enzyme digest and ligation) 9
2.2.1.5 製備勝任細胞 (Competent cell) 10
2.2.1.6 大腸桿菌轉型作用 (Transformation) 10
2.2.2 蛋白質濃度測量 10
2.2.3 蛋白質膠體電泳 (SDS-PAGE) 11
2.2.4 S100A4重組蛋白質之表現及純化 11
2.2.4.1 重組蛋白質之誘導 (Induction) 11
2.2.4.2 親和性鎳離子螯合樹脂色層分析法純化重組蛋白 12
2.2.4.3 分子篩選層析 (Size-exclusion chromatography) 13
2.2.5 感應耦合電漿質譜分析儀 (ICP-MS)原理及樣品製備 13
2.2.6 圓二色光譜原理及樣品製備 (Circular dichroism, CD) 14
2.2.7 S100A4突變株蛋白質的結晶 14
2.2.7.1蛋白質結晶原理及介紹 14
2.2.7.2 S100A4突變株蛋白質晶體X-ray繞射數據的收集 15
2.2.8 S100A4 蛋白質結構模型的重建 15
2.2. 9 X光小角度散射 (Small Angle X-ray Scattering, SAXS) 16
2.2.9.1 SAXS原理的介紹 16
2.2.9.2 SAXS樣品的製備 17
2.2.9.3 SAXS數據的收集 18
2.2.9.4 SAXS數據分析及處理 18
第三章 結果 19
3.1 重組蛋白質質體之建構 19
3.2 重組蛋白質之純化 19
3.3 S100A4野生株和突變株鈣離子含量測定 20
3.4 S100A4野生株和突變株二級結構的判定 20
3.5 S100A4突變株蛋白質的結晶與數據收集 21
3.6 S100A4 蛋白質結構模型的重建 21
3.7 S100A4突變株蛋白質SAXS數據的收集和處理 21
第四章 討論 23
第五章 結論 28
圖 29
表 46
參考文獻 53
附錄 61
附錄2.1藥品與廠商 61
附錄2.2 溶液配製 64
附錄2.3 CD SPECTRA OF PROTEINS WITH CORRESPONDING SECONDARY STRUCTURES. 67
附錄3.1 PROTEIN SEQUENCE OF S100A4 WILD TYPE AND MUTANTS USED IN THIS STUDY. 68
附錄3.2 CALIBRATION CURVE OF ICP-MS ASSAY. 69
附錄3.3 KRATKY PLOT OF SAXS SCATTERING CURVES. 70
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