S100B蛋白質可干擾S100A6與RAGE V domain結合並調控細胞增生的生化活性

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研究生：	宋信諺 Sung, Hsin-Yen
論文名稱：	S100B蛋白質可干擾S100A6與RAGE V domain結合並調控細胞增生的生化活性 S100B modulates cell proliferation by interfering with S100A6-RAGE V-domain interaction
指導教授：	余靖 Yu, Chin
口試委員:	蘇士哲 Sue, Shih-Che 楊立威 Yang, Lee-Wei 孫仲銘 Sun, Chung-Ming
學位類別：	碩士 Master
系所名稱：	理學院 - 化學系 Department of Chemistry
論文出版年：	2021
畢業學年度：	109
語文別：	中文
論文頁數：	74
中文關鍵詞：	S100B蛋白質、S100A6蛋白質、RAGE 蛋白質、核磁共振光譜、HADDOCK結構計算、WST-1 assay細胞線實驗
外文關鍵詞：	S100B protein, S100A6 protein, RAGE protein, NMR HSQC, HADDOCK structure calculation, WST-1 Assay
相關次數：	點閱：1 下載：0
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S100蛋白質家族是分子量小的酸性蛋白質家族，分子量落在10kDa，多存在於脊椎動物的組織與細胞當中。S100蛋白家族具有EF hand結構( helix-loop-helix)，可以與鈣離子結合，產生構型變化，使得疏水性區域得以與目標蛋白或分子結合，產生特定生理功能。S100蛋白家族通常能形成多聚體，例如:同質二聚體，且由於S100蛋白結構的相似性，彼此也有可能形成異質二聚體。此外，S100蛋白彼此間，結構上最相異的部分在於Hinge區域 (用與連接helix2 與helix3)，hinge區同時也是目標蛋白主要結合位置之一，因為hinge區域結構的不同，不同的S100蛋白具有不同的特性。
本篇論文研究mS100A6與S100B的關係，兩種蛋白質同質二聚體皆能與RAGE (Receptor for advanced glycation endproducts)結合，使得RAGE蛋白Cytoplasmid domain相互靠近，進而產生autophosphorylation，經由訊號傳遞反應，造成細胞增生。此外，已有研究顯示，mS100A6與S100B能夠相互結合成異質二聚體，透過研究mS100A6與S100B的結合位向，便能知曉S100B 是否能夠作為抑制劑，抑制mS100A6-RAGE V-domain 的交互作用。
因此，本實驗透過大腸桿菌表現與純化mS100A6與S100B蛋白質，並搭配M9培養液體(15N標記)觀察特定蛋白質的訊號，透過NMR HSQC 二維核磁共振滴定實驗，得知mS100A6與S100B蛋白質在生成異質二聚體時，兩蛋白質所使用的胺基酸位置，再將光譜上得知的胺基酸訊號作為HADDOCK軟體的輸入參數，進而計算出最佳的蛋白質異質二聚體三維結構圖。經由PyMOL軟體將異質二聚體的三維結構圖與已發表的mS100A6-RAGE V-domain結構圖進行疊圖分析，最終發現S100B可以當作抑制劑，阻擋mS100A6-RAGE V-domain 的交互作用，抑制細胞的增生。
最後，在利用細胞實驗WST-1 Assay實際進行細胞增生率的量測，採用SW480 Cell line進行，分別使用四種條件，第一組為控制組，不添加S100蛋白質，第二組為添加mS100A6作為條件，第三組為添加S100B，最後一組為加入mS100A6-S100B異質二聚體，比較這四種條件，可以得知異質二聚體的存在確實可以降低細胞的增生率，因此，可以進一步證實S100B可以作為抑制mS100A6-RAGE V-domain 的交互作用的抑制劑。

S100 proteins are small-sized acidic proteins. They own a characteristic structure which is called an EF-hand structure. The EF-hand structure is used to bind with calcium ions. After binding with calciumn ions, the structures of the S100 proteins are altered, which brings about the exposure of the hydrophobic area of the proteins. The hydrophobic parts of the proteins are often used to bind with the target proteins or molecules, which causes the following downstream physiological reactions. For example, mS100A6 and S100B can bind with the target protein which is RAGE V-domain to induce the cell proliferation. The S100 proteins are prone to form homodimers. In addition, given that they share similar structures, the S100 proteins can form heterodimers with one another as well.
From the previously reported literature, mS100A6 homodimer can interact with RAGE V-domain and induce the cell proliferation. In addition, as per the reported paper, mS100A6 can also interact with S100B to form a heterodimer. The purpose of this thesis, therefore, is to find out the orientation of S100B binding to mS100A6 and the three-dimensional structure of the heterodimer. S100B is the potential inhibitor to block the interaction between mS100A6 and RAGE V-domain.
In this thesis, we utilize the plasmid from E-coli as a vector transferred into the E-coli cells and induce the cells to express mS100A6 and S100B proteins by adding IPTG. After the expression and the purification procedures of mS100A6 and S100B proteins in the M9 media, we can get the NMR HSQC spectra of the specific proteins. After the analysis of the spectra, we are able to <span class="highlighter highlight-on">label</span> all the residues used in the interface during the formation of the heterodimer of mS100A6 and S100B. We input the residues as parameters into the HADDOCK software and we can get the calculated structure afterwards.
We draw a conclusion that S100B structurally blocks the interaction between mS100A6 and RAGE V-domain after overlapping the newly calculated structure with the previously reported structure of mS100A6 and RAGE V-domain.
Lastly, by WST-1 Assay, we can test the conditions for the cell growth in the presence and absence of the mS100A6-S100B heterodimer. The result shows that the SW480 cells grow more efficiently through the interaction between mS100A6 homodimer and RAGE V-domain. The growth rate goes down with the heterodimer involved. S100B can be an inhibitor of an interplay between mS100A6 and RAGE V-domain.

摘要………………………………………………………………………………Ⅰ
Abstract…………………………………………………………………………Ⅱ
誌謝………………………………………………………………………………Ⅲ
目錄………………………………………………………………………………Ⅳ
圖目錄……………………………………………………………………………Ⅷ
表目錄……………………………………………………………………………Ⅹ
縮寫表……………………………………………………………………………XI
第一章前言………………………………………………………………………1
1.1生物核磁共振實驗之介紹……………………………………………………1
1.1.1核磁共振光譜之樣品製備…………………………………………………2
1.1.2判定蛋白質骨架胺基酸序列………………………………………………4
1.1.3判定蛋白質分子的支鏈序列………………………………………………7
1.2計算蛋白質結構的限制條件…………………………………………………9
1.2.1距離限制條件(NOE Distance Constraints)……………………………9
1.2.2雙面角限制條件……………………………………………………………10
1.2.3氫鍵限制條件 (Hydrogen Bond Constraints)…………………………11
1.3 ARIA/CNS結構計算…………………………………………………………12
1.4 HADDOCK 介紹………………………………………………………………14
1.5 S100蛋白質家族結構與特性………………………………………………16
1.6 S100蛋白質家族與鈣離子結合產生構型改變……………………………17
1.7 S100A6蛋白質家族結構與特性……………………………………………18
1.8 S100B蛋白質家族結構與特性……………………………………………19
1.9 RAGE蛋白質的結構與特性………………………………………………21
1.10實驗動機……………………………………………………………………22
第二章 實驗材料與方法………………………………………………………24
2.1 mS100A6蛋白質之基因取得………………………………………24
2.1.1 mS100A6蛋白質表現………………………………………………24
實驗儀器……………………………………………………………………25
實驗步驟……………………………………………………………………25
2.1.2 mS100A6蛋白質純化…………………………………………………26
實驗儀器……………………………………………………………………26
實驗步驟……………………………………………………………………26
2.2 S100B蛋白質之基因取得………………………………………………28
2.2.1 S100B蛋白質表現……………………………………………………28
實驗儀器……………………………………………………………………28
實驗步驟……………………………………………………………………29
2.2.2 S100B蛋白質純化…………………………………………………30
實驗儀器……………………………………………………………………………30
實驗步驟……………………………………………………………………………30
2.3蛋白質基本性質鑑定…………………………………………………………32
2.3.1蛋白質電泳技術(SDS-PAGE)………………………………………………32
實驗步驟……………………………………………………………………………32
2.3.2 蛋白質質量鑑定……………………………………………………………34
實驗儀器……………………………………………………………………………34
實驗步驟……………………………………………………………………………34
2.3.3 蛋白質濃度的測定…………………………………………………………34
2.3.4 二維核磁共振實驗…………………………………………………………35
實驗儀器……………………………………………………………………………35
實驗步驟……………………………………………………………………………35
2.3.5 二維核磁共振滴定實驗 (HSQC titration)……………………………36
2.3.6 蛋白質分子的結構計算……………………………………………………36
2.3.7 WST-1 cell proliferation assay………………………………………36
實驗步驟……………………………………………………………………………37
第三章 結果與討論………………………………………………………………38
3.1 蛋白質的純化…………………………………………………………………38
3.1.1 蛋白質大量表現……………………………………………………………38
3.1.2  mutant S100A6 (C3S)……………………………………………………39
3.1.3 mS100A6蛋白質純化………………………………………………………40
3.1.4 S100B蛋白質純化…………………………………………………………42
3.2 蛋白質質量鑑定……………………………………………………………44
3.2.1蛋白質除鹽…………………………………………………………………44
3.2.2 蛋白質質量鑑定…………………………………………………………45
3.3 mS100A6蛋白質、S100B蛋白質二維1H-15N HSQC光譜……………………47
3.4 核磁共振量測蛋白質與蛋白質的交互作用原理…………………………48
3.5 mS100A6蛋白質與S100B蛋白質交互作用…………………………………51
3.5.1 核磁共振滴定實驗介紹…………………………………………………51
3.5.2實驗前尿素前處理 (Dialysis-urea treatment)………………………51
3.5.3未標定(Unlabeled) S100B蛋白質滴定標定(Labeled) mS100A6蛋白質…52
3.5.4未標定(Unlabeled) mS100A6蛋白質滴定標定(Labeled) S100B蛋白質…54
3.6 mS100A6與S100B蛋白質結構…………………………………………………56
3.6.1 mS100A6與S100B蛋白質複合結構…………………………………………57
3.6.2 mS100A6與S100B蛋白質複合結構與反應作用討論………………………60
3.7利用WST-1 Assay研究對細胞生物活性的影響………………………………62
結論…………………………………………………………………………………63
參考文獻……………………………………………………………………………65
附錄

圖目錄
圖1-1 (左)HNCA與(右)HN(CO)CA…………………………………………………5
圖1-2 (左)HNCACB與(右) CBCA(CO)NH…………………………………………6
圖1-3 (左)HN(CA)CO與(右)HNCO………………………………………………7
圖1-4 (左) HBHA(CO)NH、(中) HC(CO)NH 、(右) CC(CO)NH…………………8
圖1-5利用HC(CO)NH、CC(CO)NH判定valine的支鏈……………………………8
圖1-6 (左) HCCH-TOCOSY與(右) HCCH-COSY……………………………………9
圖1-7 W0 與W2示意圖……………………………………………………………10
圖1-8 雙面角示意圖………………………………………………………………11
圖1-9 NMR獲得結構示意圖………………………………………………………12
圖1-10 ARIA 結構計算流程圖……………………………………………………13
圖1-11 Simulated Annealing流程圖……………………………………………14
圖1-12 S100 EF hand示意圖……………………………………………………17
圖1-13 S100A4與鈣離子結合示意圖……………………………………………18
圖1-14 mS100A6三維結構圖 (PDB ID:2M1K) 與S100A6胺基酸序列…………19
圖1-15 S100B三維結構圖 (PDB ID: 1UWO) 與S100B胺基酸序列……………20
圖1-16 RAGE蛋白質結構圖……………………………………………………21
圖1-17 mS100A6與RAGE V-domain的結合反應…………………………………22
圖3-1 不同乳酸濃度下的基因表現………………………………………………38
圖3-2 S100A6蛋白質序列…………………………………………………………39
圖3-3 mS100A6 Q XL 陰離子交換管柱層析圖譜………………………………40
圖3-4 mS100A6陰離子交換管柱後的SDS-PAGE…………………………………40
圖3-5 S100A6 疏水性管柱的層析圖譜…………………………………………41
圖3-6 mS100A6蛋白質疏水性管柱後的SDS-PAGE結果…………………………41
圖3-7 S100B Q XL 陰離子交換管柱層析圖譜…………………………………42
圖3-8 S100B蛋白質陰離子交換管柱後的SDS-PAGE結果………………………42
圖3-9 S100B Q XL 陰離子交換管柱層析圖譜…………………………………43
圖3-10 S100B蛋白質粒徑篩析管柱後的SDS-PAGE結果………………………43
圖3-11 mS100A6高效能液相層析儀層析圖譜…………………………………44
圖3-12 S100B高效能液相層析儀層析圖譜……………………………………45
圖3-13 S100A6 、S100B、胺基酸序列………………………………………45
圖3-14 mS100A6蛋白質的ESI Mass測量………………………………………46
圖3-15 S100B蛋白質的ESI Mass測量…………………………………………46
圖3-16 mS100A6蛋白質二維  1H-15N HSQC光譜………………………………47
圖3-17 S100B蛋白質二維  1H-15N HSQC光譜…………………………………48
圖3-18 fast exchange rate與slow exchange rate的光譜呈現……………49
圖3-19 Fast exchange rate、Intermediate exchange rate 、Slow exchange rate的說明…………50
圖3-20 urea treatment 步驟流程圖…………………………………………52
圖3-21 1:1 Bound form mS100A6 (藍)與free form mS100A6光譜圖(紅)之疊圖…………53
圖3-22 (A) 1:1 Bound form mS100A6 (藍)與free form mS100A6光譜圖(紅)之疊圖(B) S100A6的三維結構圖…………54
圖3-23 1:0.5 Bound form S100B (黃)與free form S100B光譜圖(紅)之疊圖.55
圖3-24 (A) 1:0.5 Bound form S100B(黃)與free form S100B光譜圖(紅)之疊圖
(B) S100B的三維結構圖……………56
圖3-25 mS100A6-S100B蛋白質複合物結構………………………………………58
圖3-26 mS100A6-S100B結構Ramachandran plot………………………………59
圖3-27 mS100A6-RAGE V-domain蛋白質複合物結構 (結構來源為PDBID: 2M1K)60
圖3-28 S100B 蛋白質阻斷mS100A6-RAGE V-domain交互作用(1)……………61
圖3-29 S100B 蛋白質阻斷mS100A6-RAGE V-domain交互作用(2)……………61
圖3-30 WST-1 Assay 研究對細胞生物活性之影響…………………………62

表目錄
表1-1 NMR與X-ray之比較……………………………………………………2
表2-1 mS100A6 純化過程使用的緩衝液配置方法………………………28
表2-2 S100B純化過程使用的緩衝液配置方法…………………………31
表2.3 SDS Running Buffer 配置………………………………………32
表2.4 Staining Solution的配置……………………………………33
表2.5 Destaining Buffer的配置……………………………………33
表2.6(上層)焦急凝膠成分……………………………………………33
表2.7 (下層) 分離凝膠成分…………………………………………33
表2.8 WST-1 Assay操作條件與濃度…………………………………37









 

                                

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