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研究生:洪國維
研究生(外文):Kuo-Wei Hung
論文名稱:人體纖維母細胞生長因子受體之第二功能區塊在結構與性質的探討
論文名稱(外文):Solution Structure and Property of the D2 Domain of the Human Fibroblast Growth Factor Receptor
指導教授:余靖余靖引用關係
指導教授(外文):Chin Yu
學位類別:博士
校院名稱:國立清華大學
系所名稱:化學系
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:英文
論文頁數:148
中文關鍵詞:纖維母細胞生長因子第二功能區塊β-摺板蛋白液態結構再摺疊核磁共振
外文關鍵詞:Fibroblast growth factorsD2 domainβ-sheet proteinsolution structurerefoldNMR
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人體纖維母細胞生長因子(FGF)在細胞中所調節的機制過程非常廣泛,其生物活性主要是藉由和細胞表面受體(FGF receptor)之間的結合來傳達.在本研究當中,我們已經成功地利用大腸桿菌(E. coli)將表面受體中的第二功能區塊(domain 2)蛋白表達出來,並經由各種純化步驟得到大量的高純度蛋白.在蛋白質結構的初步鑑定上,經由圓二色光譜儀(circular dichroism, CD)和化學位移預測法(chemical shift index, CSI)我們可以得知, 第二功能區塊蛋白主要是由9個β摺板(β-sheet)所組成.至於第二功能區塊蛋白的生物活性,則是透過恆溫滴定熱卡計(isothermal titration calorimetry, ITC)和尿素變性實驗(Urea-induced denaturation),來加以證實第二功能區塊蛋白和配體(ligand,包括FGF, heparin和SOS)之間的結合作用力.
此外,我們亦根據在核磁共振(NMR)實驗上所得之數據,經由電腦計算的方式(ARIA-CNS)將第二功能區塊蛋白在水溶液中的三度空間結構(three-dimensional structure)解出,以便研究第二功能區塊蛋白與配體之間的相互作用力,並進一步透過化學位移擾動(chemical shift perturbation)實驗來找出參與結合的殘基位置(binding site),達到將結合作用區域最小化(minimization)的目的.所得到的結果,將會在藥物開發和相關疾病治療上有相當的貢獻.另一方面,在蛋白質分子狀態(molecular state)得探討上,我們利用高速中壓色層分析系統(fast performance liquid chromatography, FPLC)來偵測第二功能區塊蛋白本身以及與配體之間的結合/分離狀態 (association/dissociation state),以便進一步了解人體纖維母細胞生長因子之系統活化過程.
Fibroblast growth factors (FGFs) regulate a wide range of important cellular processes. The biological activities of FGFs are mediated by cell surface receptors or FGFRs. We have expressed the FGF-binding (or D2) domain of FGFR in Escherichia coli in high yields (10 mg /liter) and recovered the D2 protein by dissolving in 8 M urea, subsequently refolding on the nickel affinity column and purification using heparin-sepharose affinity resin. Far UV circular dichroism data and 1Hα, 13Cα, 13Cβ and 13CO chemical shift indices suggested that the D2 domain is an all beta-sheet protein consisting of 9 beta-strands. Isothermal titration calorimetry and equilibrium urea unfolding experiments showed that the recombinant D2 domain was in a biologically active conformation and binds strongly to its ligand FGF and to the heparin analog, sucrose octasulfate (SOS).

Using a variety of triple resonance NMR experiments, assignments of the 1H, 15N and 13C resonances in the D2 domain have been completely accomplished. The three-dimensional structure of the D2 domain was calculated using distance-geometry followed by simulated annealing techniques with ARIA-CNS. RDC restraints were also incorporated for structure refinements. 15N T1, T2 and steady-state NOE values at two magnetic fields (500 MHz and 800 MHz) further defined regions of the D2 domain in rigid structure formation as well as with flexible surface loops.

The binding regions of hFGF-1 and SOS on the isolated D2 protein were characterized using 1H-15N HSQC perturbation experiments and compared these specific ligand-binding interactions with the related crystal complex structures. A peptide spanning residues 11 to 28 of the isolated D2 domain sequence was synthesized to identify the specific ligand-binding interactions between the D2 domain and hFGF-1. Size exclusion fast performance liquid chromatography (FPLC) provides a direct approach to monitor the association/ dissociation state of the D2 domain with/ without SOS and hFGF-1 molecules.
Chapter 1. Introduction

1.1 The Function and Structure of FGFs ……………………...……… 1
1.2 FGFs and Heparin Binding ……………………………………….. 5
1.3 Role of Heparin in the Cell Proliferation Activity of FGFs ……… 7
1.4 FGF Receptor(s)-Ligand Interaction ………………...…………… 9
1.5 Significance of the D2 Domain in FGF Receptor ………………... 18


Chapter 2. Molecular Cloning, Overexpression, Purification and Characterization of the D2 Domain of the Human Basic Fibroblast Growth Factor Receptor

2.1 Introduction ………………………………………………………. 25
2.2 Materials and Methods …………………………………………… 27
2.3 Results and Discussions ………………………………...………… 32
The D2 protein was expressed as inclusion bodies ………………... 32
Purification of the D2 domain ……………………………………... 35
Secondary structure of the D2 domain …………………………….. 38
Stability of the D2 domain ……...………………………………….. 39
Heparin binding affinity …………………………………………… 44
D2 domain-FGF interaction ………...……………………………… 46
NMR analysis of the D2 domain …………………………………... 48

Chapter 3. Resonance Assignments of the D2 Domain of the Human Basic Fibroblast Growth Factor Receptor

3.1 Introduction ………………………………………………………. 50
3.2 Materials and Methods …………………………………………… 51
3.3 Results and Discussions …………………………………………... 53
Triple-resonance experiments of the D2 domain …………………... 53
Heteronuclear experiments of the D2 domain ……………………... 56
Reverse-selective 15N-labeling experiments of the D2 domain ……. 59
Extent of assignments and data deposition of the D2 domain ……... 63
Chemical Shift Index ………………………………………………. 63


Chapter 4. Structure Determination and 15N NMR Relaxation Studies of the D2 Domain of the Human Basic Fibroblast Growth Factor Receptor

4.1 Introduction ……………………………………………....………. 71
ARIA- CNS ………………………………………………..….…... 71
Residual dipolar coupling constants (RDCs) ………………...……. 72
15N NMR relaxation …………………………………….……..…... 73
4.2 Materials and Methods …………………………………..….…… 75
Constraints for structure calculation ……………………..…..……. 75
Structure calculation ………………………………………..….….. 81
Measurement of NMR relaxation times ………………….….….… 82
4.3 Results and Discussions ………………………………….…..…... 85
Distance restraints………………………………………………….. 85
Dihedral angle restraints…………………………………….…..…. 87
Long range restraints …………………………………………...…. 87
Parameters for structure calculations …………………………...…. 89
Structure calculations and quality of calculated structures ……...… 89
Structure description and comparison between solution andcrystal structures ……………….………………………………..… 98
15N NMR relaxation measurements ……………………………...... 103


Chapter 5. Molecular Interaction of the D2 Domain of the Human Basic Fibroblast Growth Factor Receptor

5.1 Introduction ……………………………………………………... 107
Characterization of Binding Sites ………………………………... 107
Investigation of oligomerization …………………………………. 109
Structure-Activity Relationship (SAR) …………………………... 111
5.2 Materials and Methods ………………………………………….. 112
5.3 Results and Discussions ………………………………………… 114
D2/ hFGF1 interactions …………………………………………... 114
D2/ SOS interactions ……………………………………………... 122
Minimization of hFGF-1 binding site ……………………………. 125
Investigation of oligomerization …………………………………. 129


Conclusions ………………………………………………………. 132
References ………………………………………………………… 134
Publication List…………………………………………………… 148
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