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研究生： 王漢民
Han-Min Wang
論文名稱： 人體纖維母細胞生長蛋白的摺疊探討
Folding Studies on the Human Acidic Fibroblast Growth Factor
指導教授： 余靖
Chin Yu
口試委員:
學位類別： 博士
Doctor
系所名稱： 理學院 - 化學系
Department of Chemistry
論文出版年： 2003
畢業學年度： 91
語文別： 中文
論文頁數： 193
中文關鍵詞： 纖維母細胞生長蛋白 、促進細胞增生 、摺疊 、澱粉狀蛋白 、纖維 、氫-氘交換 、分子伴護子 、變性態結構
外文關鍵詞： fibroblast growth factor, mitogenic, folding, amyloid, fibril, H/D exchange, molecular chaperone, denatured structure
相關次數： 點閱：2  下載：0 
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    • 人體酸性纖維母細胞生長蛋白(hFGF-1)為22種以上結構相似的纖維母細胞生長蛋白家族的一種，具有廣泛生理及病理活性的蛋白質，其活性包括促進細胞增生、細胞分化、促進血管生成、以及促進傷口癒合等。纖維母細胞生長蛋白受體的二聚化一直以來都被認為是誘發纖維母細胞生長蛋白的細胞訊息傳遞的機制。因此，我們利用細胞增生實驗來推衍出纖維母細胞生長蛋白的促進細胞增生活性的機制。在實驗中，我們所使用的配位基-八硫酸基蔗糖(Sucrose Octasulfate; SOS)表現出增加纖維母細胞的促進細胞增生活性卻並不會造成纖維母細胞的二聚化。此外，我們也利用了不會與肝磷酯結合的突變種人體酸性纖維母細胞生長蛋白(C131D)來進行實驗，結果顯示人體酸性纖維母細胞生長蛋白的促進細胞增生活性並不需要藉由二聚化來啟始。
    蠑螈酸性纖維母細胞生長蛋白(nFGF-1)亦是纖維母細胞生長蛋白家族的一員。在實驗中，我們發現此蛋白質會受溫度升高的影嚮而變性，並發現在開散過程中有中間體的存在。當溫度到達約攝氏六十度時，這些中間體變會進一步地聚集在一起，形成具有高度結構性的澱粉狀蛋白纖維。

    利用氫-氘交換實驗，我們發現：在弱酸性的環境下，纖維母細胞生長蛋白的穩定性比在中性環境下低，而此低穩定性的蛋白質可與分子伴護子作用。當分子伴護子蛋白與弱酸性環境下的纖維母細胞生長蛋白結合時，會試圖將它開散。而在重摺疊的實驗中，我們也發現分子伴護子會加速在酸性環境下的纖維母細胞生長蛋白的摺疊速率而非在中性環境下。

    最後，我們利用蛋白質在變性環境下的氫-氘交換實驗獲得了人體酸性纖維母細胞生長蛋白變性態的殘餘結構。這些區域性的殘餘結構很可能提供了蛋白質摺疊的起源很重要的訊息。

    Human acidic fibroblast growth factors (aFGF-1) is a member of the fibroblast growth factor family which consists of at least 22 structurally related polypeptides with a wide range of physiological and pathological activities such as cell growth, differentiation, neovascularization and wound healing. Dimerization of the fibroblast growth factor receptor (FGFR) is proposed to be a key event in the transduction of the FGF-induced cellular signals. We have performed cell culture mitogenic assay to propose the mechanism of this biological activity. The ligand (SOS) we examined in this study was found to have mitogenic activity but can not dimerize FGF-1. We also apply a mutant hFGF-1 (C131D) which can not bind to heparin but, shows the mitogenic activity. The activity may not need to be induced by dimerization of FGF-1. The FGF-1 may be in a near-native state under physiological conditions and thus have the ability to transport its self across the membrane.
    nFGF-1 is a member of FGF-1 family. nFGF-1 is found to undergo heat-denature process with accumulation of late-intermediate at temperature around 60℃. Such an intermediate may further assemble to each other to form a superstructured amyloid fiber.

    With the performances of hydrogen-deuterium exchange experiments under acidic and neutral conditions, FGF-1 is found to be less stable in the acidic condition. This unstable species is found to interact with molecular chaperone-GroEL. GroEL recognizes the near-native state hFGF-1 in pH5.0 and unfolds it. Kinetic studies also indicate that GroEL can accelerate hFGF-1 refolding process under pH5.0 condition meaning that the refolding of hFGF-1 in acidic condition may via the accumulation of intermediate(s).

    Finally, we performed the H/D exchange experiments in the denatured hFGF-1. The results show that under 4 M urea and low pH (~4.5) condition, hFGF-1 possesses residual structures. These residual structures are mostly in sequential and hydrophobic. Besides, they are close to each other in the tertiary structure. They may be crucial to the initiation of protein folding.

    1. Introduction 1.1 Protein Folding and Disease………………………………………1 1.2 Protein Folding Models…………………………………………...4 1.3 Intermediates in Protein Folding........................9 1.4 Molecular Chaperone and Its Function....................24 1.5 Hydrogen-Deuterium Exchange.............................37 1.6 Acidic Fibroblast Growth Factor (aFGF-1)................38 1.7 Importance of understanding folding/unfolding process in b-sheet proteins..............................................42 2. Expression, Purification, Characterization of aFGF-1 2.1 Introduction................................................61 2.2 Materials and Methods.....................................................64 2.3 DNA sequence analysis....................................................69 2.4 Expression of hFGF-1 and 15N-hFGF-1.....................71 2.5 Purification of hFGF-1 using Heparin Affinity Column....73 2.6 Primary Sequence Analysis of hFGF-1.....................76 2.7 ESI-Mass Analysis....................................................80 2.8 Fluorescence Spectroscopic Analysis.....................81 2.9 Circular Dichroism Spectroscopic Analysis...............82 2.10 Nuclear Magnetic Resonance Spectroscopic Analysis......82 3. Oligomerization of nFGF-1 is not Prerequisite for Its Cell Proliferation Activity 3.1 Introduction............................................84 3.2 Materials and Methods...................................87 3.3 Stabilities of Ligand-Bound nFGF-1......................90 3.4 Mitogenic Activities of FGF-1 and Its Mutant Type.......92 3.5 Oligomerization nFGF-1 May not be Prerequisite for Its Cell Proliferation Activity......................................96 4. Amyloid-Like Fibril Formation in an all b-Barrel Protein Involves the Formation of Partially Structured Intermediate(s) 4.1 Introduction............................................101 4.2 Materials and Methods...................................102 4.3 Temperature-Induced Aggregation.........................109 4.4 Identification of the Amyloid-Like Fibrils..............110 4.5 Ultrastructure of the Thermal-Induced Amyloid Fibrils...113 4.6 Thermal Unfolding of nFGF-1.............................116 4.7 Formation of Partially Structured State(s)..............119 4.8 Structural Interactions in the Thermal-Induced Amyloid Fibrils.....................................................123 4.9 Model for the Thermal–Induced Amyloid-Like Fibril Formation in nFGF-1.........................................126 5. pH-Induced Intermediate(s) of hFGF-1 and Its Interaction(s) with Molecular Chaperon 5.1 Introduction................................................128 5.2 Materials and Methods...................................130 5.3 pH-Induced Thermo-Intermediate(s) of hFGF-1.............135 5.4 Structural Difference(s) in Native/Near-Native pH-Range..143 5.5 Interaction(s) between native/near-native hFGF-1 and GroEL.......................................................148 5.6 Kinetic Enhancement in the hFGF-1 Refolding Process by GroEL.......................................................156 6. Characterization of hFGF-1 Structure in the Different Denatured State(s) 6.1 Introduction............................................160 6.2 Materials and Methods.....................................................160 6.3 Residual Structure in the Urea-Induced Denatured State(s).........................................................162 6.4 Residual Structure in the TFE-Induced Denatured State(s).........................................................169 References..................................................173 Publication List............................................193

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