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研究生:謝嘉芬
論文名稱:利用雷射光鉗技術量測整合素(alphaIIb)(beta3)和蛇毒蛋白(rhodostomin)的單分子交互作用
論文名稱(外文):Using optical tweezers-based technologies to assess single-molecular pair interactions between integrin (alphaIIb)(beta3) and the disintegrin rhodostomin
指導教授:林奇宏林奇宏引用關係
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:微生物暨免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2003
畢業學年度:91
語文別:英文
論文頁數:55
中文關鍵詞:整合素(alphaIIb)(beta3)蛇毒蛋白動力學平衡單一分子對作用力
外文關鍵詞:integrin (alphaIIb)(beta3)rhodostomindynamicsingle binding force
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Integrin,扮演著物理性與訊息性連結胞外與胞內傳遞者的角色。在以前的研究結果指出,要活化integrin且使其有生理活性,需要一個細胞由內而外的訊息傳導。但是,integrin要活化的整個過程是如何發生的,需要哪些條件,都尚未明朗。
在我們的研究當中,我們利用雷射光鉗這個實驗平台,來探討受體integrin (alphaIIb)(beta3)和其配體(蛇毒蛋白rhodostomin)之間分子層次的動力學特性。
在沒有內生integrin (alphaIIb)(beta3)的中國倉鼠卵母細胞株上,我們使其個別表現了原生與數種無法被磷酸化的突變integrin (alphaIIb)(beta3)重組蛋白。藉由雷射光鉗這個實驗平台,我們更進一步的量測到單一integrin (alphaIIb)(beta3)和rhodostomin分子對的生物力。並且,我們除了自己架設雷射光鉗這個平台之外,又更添加了數種不同功能的系統,例如optical force microscopy。藉由這含有多種功能的實驗平台,我們可以操控生物體,測量生物分子間的相互關係,和生物分子之間的作用力…等等。
在我們的實驗當中,我們發現了會表現integrin (alphaIIb)(beta3)在細胞膜上的中國倉鼠卵母細胞株和表面有rhodostomin的微粒子,在其剛接觸的90秒內,兩者的作用力會不斷增加。這或許是因為有更多的分子參與反應,或者是引發了細胞內一連串的反應。當這群integrin (alphaIIb)(beta3)與rhodostomin產生更強作用力的過程中,我們發現在integrin (alphaIIb)(beta3)胞內部分位於第747和759個位置的的酪氨酸,其是否被磷酸化,扮演了相當重要的角色。
再則,我們除了想要初步、即時、定性的觀察integrin (alphaIIb)(beta3)與rhodostomin的相互動力學反應之外,還想更進一步的測量兩者之間單一分子對的作用力。
藉由一連串仔細謹慎的統計檢驗,我們測量到有時間性的單一分子對作用力,4.15 pN與2.54 pN。這有時間性的不同單一分子對作用力,或許是因為integrin (alphaIIb)(beta3)本身活化態的轉變、更多細胞內骨架蛋白的參與、調控蛋白的加入…等等。

Integrin receptors serve as both mechanical links and signal transduction mediators between the cell and its environments. Experimental evidence demonstrates that the activation state of integrin protein, determined by an inside-out signaling pathway, may regulate the functions of integrin in a variety of cellular activities; however, the mechanisms underlying the integrin activation process are poorly understood.
In the present study, I have utilized optical tweezers as the platform technology to investigate the kinetic behaviors of molecular interactions between integrin (alphaIIb)(beta3) and one of its disintegrin ligands, the snake venom rhodostomin. Recombinant integrin (alphaIIb)(beta3) and its mutants that are incapable of undergoing tyrosine phosphorylation at (beta3) cytoplasmic domain are expressed on the surfaces of Chinese Hamster Ovary (CHO) cells that contain no endogenous integrin (alphaIIb)(beta3) expression. The binding strength between the integrin-containing cells and the rhodostomin-coated beads was then measured by the optical tweezers. I have used conventional optical tweezers assembled in the lab, together with several functional module attached to the system, including optical force microscopy, to manipulate live cells, direct integrin-disintegrin interactions, and perform binding strength measurements.
We found that the binding force between the bulk integrin(alphaIIb)(beta3) -rhodostomin molecule populations at the cell-bead interface typically increased over the first 90-sec period of molecular interaction, presumably through recruitment of more integrin proteins and downstream effectors to the interaction site. Phosphorylations at tyrosines 747 and 759 of the cytoplasmic domain of (beta3) integrin appeared to play major roles in regulating this dynamic increase of integrin-disintegrin binding affinity at the bulk population level. Using series of analytical algorithms, we were also able to derive, from the bulk molecules data, single molecule pair binding force. Interestingly, the calculated “unit binding strength” seemed to decrease from 4.15 pN to 2.54 pN “over time” or “in a reverse relationship to the number of integrin-rhodostomin pairs participating the molecular interaction”, suggesting the presence of active and continuous modulation of the integrin protein and its associated regulatory molecular complexes, including the cytoskeleton components, that could be experimentally verified at single molecule resolution.

CONTENTS…..…………..…..…………………………………………1
FIGURE INDEX...………….…………………...………………………2
1. INTRODUTION (BIOLOGICAL SYSTEM)…………………….3
Using integrin-disintegrin as a model system to study receptor-ligand interactions.......3
The role of integrin IIb3 in platelet cells………………………………………..……………….4
Assessment of molecular interactions using optical tweezers…………………………..7
2. INTROCUTION (PHYSICAL SYSTEM)……..……..…..………7
Principles and applications of optical tweezers…………….…………………………………..7
The theoretical model of optical trapping force…………..…………………………………….8
Ray optics model……………………………………………..……………………………………..9
Electromagnetic model……………………………………………………………………………10
3. RECENT STUDIES IN CALCULATING THE OPTICAL
TRAPPING FORCE…………………………………..…….……12
Escape force method……………………………………………………………………………...12
Drag force method………………………………………….……………………………………..13
Equipartition method……………………………………….……………………………………...13
Power spectrum method………………………………………..………………………………..14
Step response method………………………………………...………………………………….14
4. THE PHOTONIC FORCE MICROSCOPE…..………..…….15
5. MATERIAL AND METHODS…………….…………………...17
Cells and gene delivery……………………….…………..……………………………………….17
Rhodostomin constructs, protein purification and protein coating…….…………………18
Immunofluorescence staining…………………………….…………………………..………….18
Detachment assay…………………………………………….……………………….……………19
Construction and use of optical tweezers…………………………….…………..……………19
Diffraction pattern system………………………………………….……………………………..19
Drag force calibration of optical tweezers………………….…………………………………..21
Lateral force retrapping for biological force measurement…………..……..………………22
Statistics……………………………………………………………………………...………………22
6. RESULTS……………….…..……………………………………..24
Expression patterns and sub-cellular distribution of the recombinant gene products in the ECR-CHO cell model…..………………………………………………….……………………24
The dynamic interaction between rhodostomin-coated beads and the recombinant
integrin proteins on the cell membrane of EcR CHO cells (Tyr→ Phe)…………..…….….24
The dynamic interaction between rhodostomin-coated beads and the recombinant
integrin proteins on the cell membrane of EcR CHO cells (Tyr→ Ala)…………...…….….25
Drag force calibration of optical tweezers…………………………………………………..27
The force distribution histogram reveals intriguing units for integrin-disintegrin binding, an implication for single molecule-pair detections…………………………………….……..27
Statistics………………………………………...…………………………………………………....27
The force distribution histogram of integrin-disintegrin mutant binding, reveals a
different quantum unit of binding force…………….…………………………………….……..28
7. DISCUSSION………...…………………………………………...38
Expression patterns and sub-cellular distribution of the recombinant gene products in
the ECR-CHO cell model…..……………………………….………………………………………38
The dynamic interaction between rhodostomin-coated beads and the recombinant
integrin proteins on the cell membrane of EcR CHO cells (Tyr→ Phe)……………..….….38
The dynamic interaction between rhodostomin-coated beads and the recombinant
integrin proteins on the cell membrane of EcR CHO cells (Tyr→ Ala)…………...…….….40
Drag force calibration of optical tweezers…………………………………………………..41
The force distribution histogram reveals intriguing units for integrin-disintegrin
binding, an implication for single molecule-pair detections………………….……………..41
Statistics………………………………………………………………………………...…………....42
The force distribution histogram of integrin-disintegrin mutant binding, reveals a
different quantum unit of binding force………………………………….……………….……..45
8. REFERENCES…………………….………….…………………..47
Figure Index
FIG. 1 THE INSIDE-OUT ACTIVATION AND OUTSIDE-IN SIGNALING OF THE INTEGRIN PROTEINS……………….4
FIG. 2 A SCHEMATIC ILLUSTRATION OF THE ROLE OF INTEGRIN IIB3 IN PLATELET AGGREGATION AND THE ROLES OF “INSIDE-OUT” AND “OUTSIDE-IN” INTEGRIN IIB3 SIGNAL TRANSDUCTION IN THESE PROCESSES……………………………………………………………………………………………………………….4
FIG. 3 A THREE-DIMENSIONAL MODEL OF THE HUMAN PLATELET INTEGRIN IIB3 BASED ON ELECTRON CRYOMICROSCOPY AND X-RAY CRYSTALLOGRAPHY (ADAIR, 2002)………………………………………...5
FIG. 4 THE RHODOSTOMIN PROTEIN………………………………………………………………………………………..5
FIG. 5 THE FIRST OPTICAL TRAP OF BIOLOGICAL MATERIALS…………………………………………………………8
FIG. 6 DIFFERENT PHOSPHORYLATION CONSTRUCTS OF INTEGRIN 3 CYTOPLASMIC DOMAIN……………….17
FIG. 7 A SCHEMATIC ILLUSTRATION OF THE EXPERIMENTAL CONFIGURATION IS SHOWN……………………..20
FIG. 8 IMMUNOFLUORESCENT ANALYSIS OF THE SUB-CELLULAR LOCALIZATION OF RECOMBINANT HUMAN INTEGRIN IIB AND3 IN ECR CHO CELLS……………………………………………………………….30
FIG. 9 THE PERCENTAGE OF BEADS BOUND WERE PLOTTED AS A FUNCTION OF RUPTURE OF TIME (Phe)….32
FIG. 10 THE PERCENTAGE OF BEADS BOUND WERE PLOTTED AS A FUNCTION OF RUPTURE OF TIME (Ala)..33
FIG. 11 THE FORCE OF OPTICAL TWEEZERS AS A FUNCTION OF LASER POWER…………………………………..34
FIG. 12 THE FORCE DISTRIBUTION HISTOGRAM OF RHODOSTOMIN WILD TYPE AND INTEGRIN IIB3……….35
FIG. 13 THE STATISTICS OF RHODOSTOMIN WILD TYPE AND INTEGRIN IIB3……………………………………..36
FIG. 14 THE FORCE DISTRIBUTION HISTOGRAM OF RHODOSTOMIN MUTANT AND INTEGRIN IIB3…….…….37

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