臺灣博碩士論文加值系統

中文摘要
ADAMalysin家族是在結構上是具有M (金屬酶蛋白功能區)、Ｄ(integrin結合功能區)與C (富含cysteine功能區)三個功能區的蛋白家族。ADAM (a disintegrin and metalloprotease)與P-III SVMP都是屬於這個家族重要成員，其中ADAM在人類的生理功能上扮演很重要的角色，舉例來說，很多文獻的證據顯示， ADAM對於一些人類的重大疾病如癌症的形成、氣喘、阿茲海默症、SARS (嚴重呼吸道症候群)等，都扮演其重要的生理角色。雖然這類蛋白質的重要性是已被公認，不過因為這類蛋白具有許多的cysteine胺基酸並且是一類細胞膜上的膜蛋白，在蛋白質的重組表現上有其困難性，所以到目前為止還沒有完整人類ADAM的結構被發表(ADAM22 細胞膜外的結構在2009年被決定)。而蛇類金屬蛋白酶的結構已被廣泛用來模擬ADAM在細胞膜表面上的行為模式。這可回推到2006年日本的研究團隊發表了第一個P-III型的蛇毒金屬酶蛋白 (VAP1) 結構並利用其模擬出ADAM的C型模型，用來表現ADAM在細胞膜表面如何辨認與裁切其受質。在這篇研究中，我們從台灣眼鏡蛇中純化、定序並決定出兩個全新的 P-III型的蛇毒金屬酶蛋白的結構- atragin 和K-like。Atragin也是屬於C型結構，而K-like呈現出一個全新的I型結構。這個明顯的結構差異主要歸因於在D功能區上雙硫鍵配對形式，這個發現也證明ADAMalysin家族中的蛋白是有可能利用其D功能區上不同的雙硫鍵配對形式來調整其M和C功能區的相對位置，進而在細胞膜表面呈現出不同的受質辨認與裁切行為。另外，這兩個蛇毒蛋白對於TNF??腫瘤壞死因子)的釋放以及細胞移動的抑制性呈現出截然不同的特性。在這篇研究中指出這兩個蛇毒蛋白對於TNF??腫瘤壞死因子)的釋放有不同的活性表現主要是來自於其M (金屬酶蛋白功能區) 活性區中的結構差異所造成;另外對於細胞移動的抑制性的差異則可能來自於在C (富含cysteine功能區)中的HVR(結構高度變異區)的結構差異。除此之外，我們還觀察到在atragin活性區中鋅的結合胺基酸 (組胺酸,Histidine)的結構改變和一個Met環的結構改變是和pH有關,而這些改變能夠解釋為何金屬酶蛋白在蛇囊(酸性環境)中，只有非常小的活性來達到毒蛇自我保護的機制。
之前的研究已經顯示atragin能夠抑制傷口愈合，主要是透過與細胞膜上整合素(integrin αvβ3)的結合。到目前為止，沒有一個non-?圂類的整合素和沒有RGD蛋白的複合結構被發表，所以決定這個複合物的結構是一個很好的研究方向，不過在經過一連串的嘗試後並沒辦法得到atragin和integrin αvβ3的複合物晶體，於是利用電子顯微鏡、分子表現蛋白功能區、小片段的蛋白鏈與整合素結合實驗以及電腦程式的模擬實驗，提出一個atragin與整合素(integrin αv?猀]3)的結合模型。
Abstract
The structures of snake venom metalloproteases (SVMPs) are proposed to be a useful model for an understanding of the structure and functional relationship of ADAM (a disintegrin and metalloprotease), a membrane-anchored protein responsible for the growth factor releasing, neuro/myogenesis and involved in cancer, Alzheimer’s and other human diseases because full-length human ADAM structures are not available now. For instance, crystal structures of three P-III SVMPs have indicated the important role of a C-shaped scaffold for substrate recognition and the shedding process of ADAM. As ADAM is known to have diverse functions, additional structural and functional study on diverse SVMP is expected to illuminate not only the mechanisms of ADAM’s action but also the venom complexity, and lead to a prospective toxin-based drug discovery. From Naja atra elapid venom, we have purified, sequenced and determined the X-ray structures of two new P-III SVMP- atragin and kaouthiagin-like (K-like). Although the monomeric structure of atragin exhibits folding similar to a known C-shaped topology of a disulfide-bridged VAP1 homodimer from C. atrox viperid venom, K-like adopts an I-shaped conformation because of the distinct disulfide pattern of the disintegrin-like (D) domain. K-like, similar to ADAM17, exhibits enzymatic specificity toward pro-TNFα with less inhibition of cell migration, but atragin shows the opposite effect. The specificity of enzymatic activity is indicated to be dominated mainly by the local structures of SVMP in the metalloprotease (M) domain, whereas the HVR region in the cysteine-rich (C) domain is involved in cell-migration activity. We also demonstrate a pH-dependent enzymatic activity of atragin that we correlate with the structural dynamics of a Zn2+-binding motif and the Met turn based on the crystal structures determined with a novel pH-jump method. This structural variation provides a basis for the lack of proteolytic activity of SVMP in a gland. Together the local structure and the combinatorial arrangement of MDC domains in SVMPs play roles in their diverse activities. ADAM might adopt a similar strategy for the shedding of a specific target available on the surface of the cell membrane.
In addition, atragin was identified to inhibit the wound healing via the binding with integrin αvβ3 in previous research. It is of interest to study the binding mode between atragin and integrin αvβ3. With crystallography, I did not get the complex crysal of integrin αvβ3 in complex with atragin because of the large sizes of the two molecules and the difficult obtainment of large amount of integrin αvβ3. I therefore utilized other indirect methods such as electron microscope, overexpression and binding assays of key domains, peptide mapping, and computer simulations to build one docking model of atragin and integrin αvβ3.

INTRODUCTION------------------------------------------ 9
SVMP (SNAKE VENOM METALLOPROTEASE)---------------------9
STRUCTURAL AND FUNCTIONAL RELATIONSHIPS OF EACH DOMAIN IN PIII SVMPS---------------------------------------------9
ADAM (A DISINTEGRIN AND METALLOPROTEASE)--------------11
STRUCTURE OF THE ECTODOMAIN OF NON-PROTEASE ADAM, ADAM22
------------------------------------------------------13
RESEARCH MOTIVE---------------------------------------13
FIGURES AND FIGURE LEGENDS----------------------------15
CHAPTER 1 PURIFICATION AND PRIMARY SEQUENCES OF THE TWO NOVEL ELAPID SVMPS, ATRAGIN AND K-LIKE----------------20
1.1 MATERIAL AND METHODS-----------------------------20
1.1.1 Purification of two P-III SVMPs atragin and K-like from Naja atra----------------------------------------20
1.1.2 Primary sequence determination------------------20
1.2 RESULTS AND DISCUSSION----------------------------21
1.2.1 Signal peptides and prodomains------------------21
1.2.2 M domains---------------------------------------22
1.2.3 D domains---------------------------------------22
1.2.4 C domains---------------------------------------22
1.2.5 The Phylogenetic tree of two PIII SVMPs, atragin and K-like------------------------------------------------23
1.3 FIGURES AND FIGURE LEGENDS------------------------25
CHAPTER 2 STRUCTURE OF ATRAGIN- UNCONVENTIONAL ZINC BINDING MOTIF-----------------------------------------33
2.1 MATERIAL AND METHODS------------------------------33
2.1.1 Purification of SVMP atragin--------------------33
2.1.2 Crystallization of atragin----------------------33
2.1.3 Data collection and structure determination of atragin ---------------------------------------------33
2.1.4 Absorption and fluorescence spectra of atragin crystals----------------------------------------------34
2.1.5 The effect of pH on enzymatic activity and fluorescence spectroscopy-----------------------------34
2.2 RESULTS AND DISCUSSION----------------------------35
2.2.1 Crystal structure of atragin--------------------35
2.2.2 Metal ions in the atragin structure (ICP-MASS)--36
2.2.3 Comparison of atragin and VAP1 structures-------36
2.2.4 The pH-dependent zinc binding motif-------------37
2.3 FIGURES AND FIGURE LEGENDS------------------------40
CHAPTER 3 COMPARISON OF STRUCTURAL AND FUNCTIONAL STUDY FOR TWO ELAPID SVMPS ATRAGIN AND K-LIKE---------------50
3.1 MATERIAL AND METHODS------------------------------50
3.1.1 Crystallization of K-like-----------------------50
3.1.2 Data collection and structure determination of K-like ---------------------------------------------50
3.1.3 Dynamic light scattering (DLS) of atragin and K-like ---------------------------------------------51
3.1.4 The metalloprotease activity on pro-TNF? assays51
3.1.5 Transwell cell migration assay------------------52
3.2 RESULTS AND DISCUSSION----------------------------52
3.2.1 Crystal structure of K-like---------------------52
3.2.2 Comparison of overall MDC architectures of atragin and K-like--------------------------------------------53
3.2.3 DLS analysis of atragin and K-like--------------54
3.2.4 Comparison of M domains of atragin and K-like---54
3.2.5 Different specificities of atragin and K-like on the proteolysis of pro-TNFα------------------------------55
3.2.6 Comparison of D domains of atragin and K-like---56
3.2.7 Comparison of C domains of atragin and K-like---57
3.2.8 Different cell-migration inhibitory activities of these two SVMPs---------------------------------------58
3.2.9 N-linked glycosylation sites on the two SVMPs---59
3.2.10 Implication of ADAM shedding mechanism --------60
3.3 FIGURES AND FIGURE LEGENDS------------------------62
CHAPTER 4 DISCUSSION OF THE BINDING MODE BETWEEN ATRAGIN AND INTEGRIN αvβ3-----------------------------------72
4.1 INTRODUCTION--------------------------------------72
Integrins ---------------------------------------------72
4.2 MATERIAL AND METHODS------------------------------73
4.2.1 Production of human integrin αvβ3 ectodomain--73
4.2.2 Production of the recombinant C domain of atragin and the VWA domain of integrin αvβ3---------------------74
4.2.3 Electron microscope and image analysis----------74
4.2.4 integrin αvβ3 binding analysis of ELISA-------75
4.2.5 Molecular docking of atragin and αvβ3 integrin76
4.3 RESULTS AND DISCUSSION----------------------------76
4.3.1 EM study of atragin and integrin αvβ3 complex-76
4.3.2 The recombinant C domain of atragin involves integrin ?悈\vβ3 binding--------------------------------------77
4.3.3 Molecular cloning and expression of the VWA domain of integrin αvβ3---------------------------------------78
4.3.4 Computer stimulated model of atragin and integrin αvβ3 complex-------------------------------------------79
4.4 FIGURES AND FIGURE LEGENDS------------------------81
APPENDIX----------------------------------------------88
A. CRYSTAL STRUCTURE OF CTXA3 AND HEXASSACHARIDE HEPARIN COMPLEX.----------------------------------------------88
B. CRYSTAL STRUCTURE OF MILK β-LACTOGLOBULIN AND VITAMIN D3 COMPLEX REVEALS A SECONDARY VITAMIN D3 BINDING SITE. ---------------------------------------------90
C. RATIONAL DESIGN FOR CRYSTALLIZATION OF MILK β-LACTOGLOBULIN AND VITAMIN D3 COMPLEX.-----------------92
D. MULTIPLE CRYSTAL STRUCTURES OF THE HUMAN AR-LBD – COACTIVATOR COMPLEX.----------------------------------94
D. MULTIPLE CRYSTAL STRUCTURES OF THE HUMAN AR-LBD – COACTIVATOR COMPLEX.----------------------------------94
E. CRYSTALLIZATION AND PRELIMINARY DATA ANALYSIS OF NPLA2-OCTASSACHARIDE HEPARIN COMPLEX AND NPLA2-DECASSACHARIDE COMPLEX.---------------------------------------------100
F. STRATEGIES FOR IMPROVEMENT OF SOLUBILITY OF THE VWA DOMAIN-----------------------------------------------102
G. VARIED SEQUENCING RESULTS ON THE POSITION 463 OF ATRAGIN --------------------------------------------104
REFERENCES-------------------------------------------106

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