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研究生:郭哲宏
研究生(外文):Kuo, Je-Hung
論文名稱:抗血管新生趨化素CXCL4及CXCL4L1的結構與功能研究:趨化素C端螺旋二級結構的空間位向如何決定其分子功能
論文名稱(外文):Structure and Function Study of the Anti-angiogenic Chemokines, CXCL4 and CXCL4L1: How the C-Terminal Helix Orientation determines the Chemokine Function.
指導教授:吳文桂
指導教授(外文):Wu, Wen-Guey
學位類別:博士
校院名稱:國立清華大學
系所名稱:生物資訊與結構生物研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:英文
論文頁數:127
中文關鍵詞:趨化分子肝素血小板因子四號血管新生
外文關鍵詞:ChemokineHeparinPlatelet factor 4Angiogenesis
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趨化素是一種分泌性蛋白質,其隸屬細胞激素的一類,此類小分子蛋白質支配多種生物性的程序。僅管在胺基酸序列的相似度不高,這些趨化素傾向形成相似且高度保留的三級結構,此結構是由三個反向排列的 beta 摺板為中心,接續為折疊在 beta 摺板上的羧基末端 alpha 螺旋結構。在結構上高度保留的特性,允許這類趨化素具有與細胞表面的醣胺多醣分子相互結合的功能,此功能攸關這些趨化素移動到生物體特定位置的能力。近期所發現且分離出更具有抑制血管新生的趨化素配體四號變異蛋白 (CXCL4L1) 是趨化素四號蛋白 (CXCL4; PF-4) 的變異型,在胺基酸序列上僅只有位於羧基末端的三個胺基酸殘基不同。在此研究中,我們利用蛋白質結晶法及X光繞射的技術成功解析出趨化素配體四號變異蛋白的結構由三維結構顯示,其羧基端的 alpha 螺旋二級結構和空間方位呈現全新結構,與以往所知的趨化素有著顯著的不同。由於不同空間位向的羧基端 alpha 螺旋結構,使整個 alpha 螺旋突出且暴露於水溶液環境中。這特殊的 alpha 螺旋結構在空間的位向,改變了趨化素整體的外型以及蛋白表面的特性,此改變導致其分子與醣胺多醣分子結合能力下降。在我們利用一系列突變蛋白質以及結合核磁共振與表面電漿共振實驗中進一步顯示,其第六十七號胺基酸殘基的變異是同時造成 alpha 螺旋結構的改變以及降低與醣胺多醣分子結合的原因,然而另外兩個胺基酸殘基則為次要角色。最後由我們的結果提出,在羧基端的 alpha 螺旋結構上的重新排列不僅支配其抗血管新生的活性,同時涉及到這類分子在細胞內擴散的效應,所有的數據支持僅僅基於蛋白質一級胺基酸序列的不同,便能使其趨化素改變蛋白質的三維結構,進而調控與細胞表面的認知。
Chemokines, a sub-family of cytokines, are small, secreted proteins that mediate a variety of biological processes. Various chemokines, despite the low degree of sequence homology, adopt remarkable conserved tertiary structure comprising an anti-parallel beta-sheet core domain followed by a C-terminal helix that packs onto the beta-sheet despite the low degree of sequence homology. The conserved structural feature allows chemokines to bind cell surface glycosaminoglycans (GAGs), crucially for recruitment of chemokines to a specific anatomical location. The recently isolated variant, CXCL4L1, is a homologue of CXCL4 chemokine (or platelet factor 4, PF-4) with potent anti-angiogenic activity and differed only in three amino acid residues of P58L, K66E and L67H. In this study, we show by X-ray structural determination that CXCL4L1 adopts a novel structure at its C-terminus. The orientation of the C-terminal helix protrudes into the aqueous space to expose the entire helix. The alternative helix orientation modifies the overall chemokine shape and surface properties. This change results in the decrease of its GAG-binding properties. A combined NMR and SPR investigation on a set of intrinsic mutants further shows that L67H is mainly responsible for the swing-out effect of the helix and the reduced GAGs binding activities, while mutations of P58L and K66E act secondarily. Our results demonstrate that the structural reorganization of the C-terminal helix mediates their anti-angiogenic effects and diffusibility. The data suggest that based on just three mutations in the primary sequence, chemokine enables to adapt an alternate C-terminal helix conformation to alter the cell surface recognition.
CHAPTER 1: GENERAL INTRODUCTION OF CHEMOKINES /1
The Chemokine Universe /1
Structural Characteristics of Chemokines /2
Binding Partners of Chemokines /4
Biological Activities of Chemokines /6
Topic: Angiostatic Chemokines CXCL4 and CXCL4L1 /10
CHAPTER 2: CXCL4 A-B DIMER AS A HEPARIN-BINDING UNIT /16
Introduction /16
Experimental Procedures /18
Sample Preparation /18
NMR Spectroscopy /19
Size-exclusion Chromatography /20
Circular Dichroism Measurement /20
SPR Heparin Binding and Competition Assay /20
Results and Discussion /22
The structural architecture was remained under reduction condition /22
Deficiency of disulfide bonds alter both oligomerization and heparin-binding affinity /23
Reduced heparin affinity was correlated with oligomerization state /23
A-B Dimer as a heparin-binding unit /24
CHAPTER 3: BIOCHEMICAL CHARACTERISTICS OF CXCL4 AND CXCL4L1 /32
Introduction /32
Experimental Procedures /33
Sample Preparation /33
Analytical Ultracentrifugation Analysis. /35
ANS binding Assay /35
Small Angle X-ray Scattering (SAXS) /35
Results and Discussion /36
Different structure and hydrophobicity of CXCL4L1 /36
CXCL4L1 exhibits as tetramer /37
Weaker heparin-binding ability of CXCL4L1 /37
CHAPTER 4: CRYSTAL STRUCTURE OF CXCL4L1 /43
Introduction /43
Experimental Procedures /44
Sample Preparation /44
Crystallization Method /44
Data Collection and Processing /44
Determination and Refinement of CXCL4L1 Structure /45
Protein Data Bank Accession Number /45
Results and Discussion /46
Crystal structure of CXCL4L1 /46
Structural divergence between CXCL4L1 and CXCL4 /47
Positive charged distribution on surface of CXCL4L1 and CXCL4 /47
C-terminal orientation of monomer structure of CXCL4L1 /48
Structural topology and hydrogen bond representation of CXCL4L1 and CXCL4 /48
Another Different Space Group of CXCL4L1 Structure /50
Alternate C-terminal Helical Orientation and Conformation Regulate Functions /51
Chemokine Heteromerization /51
CHAPTER 5: SINGLE MUTATION EFFECT ON CHEMOKINE FOLDING AND STABILITY /60
Introduction /60
Experimental Procedures /61
Sample Preparation /61
Results and Discussion /63
CXCL4L1 is not stable upon reduction of the disulfide linkages /63
Effect of single mutations on chemokine folding and stability /63
Effect of single mutations on chemokine heparin binding /64
Implications to other chemokine family /65
CHAPTER 6: STRUCTURE AND FUNCTION RELEVANCE OF CHEMOKINES /72
Introduction /72
Experimental Procedures /73
Enzyme-linked Immunosorbent Assay /73
Fluorescence Titration Assay /73
Results and Discussion /74
LPS-binding ability: structure relative to function of chemokines /74
SUPPLEMENTAL FIGURES AND TABLES /77
REFERENCES /83
APPENDIX /95
SECTION 1: PI(4,5)P2 SPECIFIC BINDING TO FGF-2 /95
Introduction /95
Experimental Procedures /97
Materials and Reagents /97
Sample Preparation /97
Isotherml Titration Calorimetry /98
NMR Spectroscopy /99
Results and Discussion /100
Quantitatively binding measurement by ITC /100
Identification phosphate group specificity on FGF-2 binding /100
Description of the FGF-2-IP(1,4,5)3 Binding Region /102
SECTION 2: THE INTERACTIONS BETWEEN FGF-2 AND MODEL MEMBERANE /109
Introduction /109
Experimental Procedures /111
Sample Preparation /111
NMR Spectroscopy / 111
Large Unilamellar Vesicles (LUVs) Preparation /112
Surface Plasmon Resonance Measurement /112
Intrinsic Fluorescence Assay /113
Docking Model by AUTODOCK /113
Results and Discussion /114
The identical binding region of FGF-2 on micelle comprising PI(4,5)P2 /114
The cholesterol/ sphingomyelin-mediated binding of FGF-2 on LUVs /115
FGF-2 directly interacts with model membrane /116
The presumed membrane-binding model of FGF-2 /117
SUPPLEMENTAL FIGURES AND TABLES /123
REFERENCES /124
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