進階搜尋


 
系統識別號 U0026-0812200913344210
論文名稱(中文) 以蛋白質體方法分析蛋白質磷酸化與激脢受質
論文名稱(英文) Proteomic Approach for the Analysis of Protein Phosphorylation and Kinase Substrates
校院名稱 成功大學
系所名稱(中) 化學系碩博士班
系所名稱(英) Department of Chemistry
學年度 95
學期 1
出版年 96
研究生(中文) 黃聖聿
研究生(英文) Sheng-Yu Huang
學號 l3891112
學位類別 博士
語文別 英文
論文頁數 161頁
口試委員 口試委員-施修明
口試委員-陳玉如
口試委員-蔡少正
口試委員-蔡美玲
指導教授-陳淑慧
中文關鍵字 定量分析  還核苷酸激脢  老鼠子宮  質譜  固定化金屬親和層析  強陰離子交換層析  蛋白質磷酸化  激脢受質 
英文關鍵字 PKA  PKG  rat uteri  kinase substrate  mass spectrometry  quantitative analysis  protein phosphorylation  IMAC  SAX 
學科別分類
中文摘要 蛋白質的磷酸化與去磷酸化組成了最基本的細胞訊息傳遞網絡,近年來質譜技術已經成為鑑定磷酸化位置的重要的工具,由於磷酸根為負電離子,當質譜以正離子模式偵測時,會抑制其質譜訊號的強度。若未經任何純化步驟,其訊號強度更會因其他非磷酸化之樣品的存在而減弱。因此在分析複雜生物樣品時,必須搭配有效的純化方式才能成功分析磷酸化蛋白質。固定化金屬親和層析法 (Immobilized metal affinity chromatography, IMAC) 已被廣泛應用在從混合樣品中純化磷酸化胜肽。其缺點是對含有較多酸性氨基酸的胜肽會有非專一性的反應,因此降低了純化磷酸化胜肽的效率。本研究包含幾個以固定化金屬親和層析法為基礎的整合分析方法,針對老鼠懷孕後期的子宮肌肉,做定性以及定量的磷酸化蛋白質分析。
第一個研究主題呈現一個簡單方便的方法來增強雷射輔助介質脫附游離化質譜 (MALDI)的偵測訊號。雖然MALDI對鹽類的耐受度比起電灑游離法(ESI)高,但是對溶於磷酸鹽緩衝液的樣品仍然有偵測上的困難。本研究發現,即使是在飽和的磷酸鹽緩衝液中,只要加入適當量的無機酸如鹽酸或硝酸,就可以大幅度提高胜肽在MALDI偵測的訊號強度。不僅如此,此方法亦可以有效去除其他高鹽類緩衝液經常產生的鹽類衍生物訊號,進而大幅度提高分析物的訊號雜訊比。
第二個主題呈現的是兩步驟的固定化金屬親和層析法來純化鑑定磷酸化蛋白質。首先,將磷酸化蛋白質與其他的非磷酸化蛋白與酵素抑制蛋白利用IMAC進行分離, 純化出的磷酸化蛋白質進行酵素消化之後,再進行第二次IMAC純化,來抓取磷酸化胜肽。此方法中,從第一步IMAC的流析到第二步IMAC,不需要做任何緩衝液交換且能夠成功鑑定出存在於細胞萃取液中百分之一的標準磷酸化蛋白。利用此法分析懷孕末期子宮樣品,可以鑑定出數個磷酸化蛋白質。
第三個研究主題(第四章)是我們利用蛋白質分離技術、雙甲基同位素標記法,搭配金屬親和層析與質譜偵測,針對經過激脢PKG活化物8-Br-cGMP處理的懷孕末期子宮做磷酸化蛋白質的定量分析。雙甲基標記法有諸多優點,其中一項是在二次質譜撞碎過程中,會有明顯a1離子的訊號提升,可用來精準地判定胜肽的N端氨基酸,因而增加鑑定的信心度。分析結果中,處理過的懷孕子宮與未處理的磷酸化胜肽比例介於0.51到1.69之間,平均值1.010.25。檢視鑑定與定量結果,發現PKG影響的蛋白質磷酸化,與抑制細胞活動、生長,肌動蛋白相關的蛋白重排,及在懷孕末期促進蛋白生成有關。
最後一個研究主題(第五章)呈現一個整合的系統方法鑑定在懷孕子宮中環核苷酸活化激脢 (PKA, PKG) 的受質。蛋白質混合物首先利用陰離子交換做分離,並以外加的去磷酸脢去除其背景磷酸化,再分別進行試管內激脢(PKA or PKG)反應。此方法免除了以往需使用放射性同位素32P進行分析的困擾。在不使用放射性同位素的情況下,亦可鑑定出數十個可能的受質以及對應的磷酸化位置。再利用前一章所建立之定量方法,來分析在PKA活化物(8-Br-cAMP) 刺激下,這些受質特定位置的in vivo磷酸化程度是否增加。其中HSP27以及filamin A為已知會被PKA磷酸化的蛋白質,在本實驗都被發現是PKA的受質且磷酸化的程度在8-Br-cAMP活化下有顯著增加。由這些數據可知,此整合方法不但對於尋找激脢受質有所助益,所得到的資訊對解釋訊息傳遞與生理現象亦有相當大的幫助。
英文摘要 Protein phosphorylation and dephosphorylation forms the basis of cell signaling networks. In order to explore the information behind these phosphorylation events, powerful mass spectrometry (MS) has been widely used and emerged as a valuable tool in the past few years. However, the MS signal intensity of phosphopeptides is relatively low due to bearing negative charges and usually being suppressed by nonphosphopeptides. For the purpose, an efficient enrichment technique is required for a successful analysis of phosphoproteins in a complicated biological sample. Immobilized metal affinity chromatography (IMAC) is one of the main tools to enrich phosphopeptides from mixtures, but it suffers from nonspecific binding of nonphosphopeptides containing many acidic amino acids when being used alone. In this study, several IMAC based strategies coupling with other separation techniques or improved detection methods are developed to qualitatively and quantitatively analyze protein phosphorylation in late gestation rat uteri.
The first topic presents a simple and convenient method to extract MALDI spectra from phosphate containing samples (chapter 2). Although MALDI-MS is known to tolerate much more salts than ESI-MS, it is still difficult to get signals from samples containing phosphate buffer which is found to have the best recovery for IMAC elution. The addition of inorganic acid such as hydrochloric acid can dramatically enhance the peptide signals even if the sample is in saturated phosphate buffer. It also efficiently eliminates signals from salt adducts that normally exist in other high salt buffers, increasing the S/N ratio of analytes.
In the second topic, a new strategy named two-step IMAC is demonstrated (chapter 3). Phosphoproteins were enriched by the first IMAC meanwhile non-phosphoproteins and undesired protease inhibitors were excluded. After trypsin digestion of extracted phosphoproteins, second IMAC was performed to enrich phosphopeptides and the elution fraction was analyzed by mass spectrometry. It is noticed that no buffer exchange is required from the first IMAC elution to second IMAC. 1% (w/w) standard phosphoprotein spiked in cell lysate can be successfully enriched by this approach and several phosphoproteins in rat uteri were identified using this approach.

In the third topic (chapter 4), a quantitative analysis of phosphoproteins in rat uteri upon the treatment of 8-Br-cGMP, a PKG activoter was presented. By coupling protein separation techniques, dimethyl labeling with IMAC enrichment and MS detection, site specific quantitation of protein phosphorylation can be achieved. Among many of the advantages of dimethyl labeling, the a1 ion enhancement can help determine the N terminal amino acid and increase the confidence of peptide identification. In the analysis of late gestation rat uteri, the abundance ratio between treat and un-treat phosphopeptide signals were determined in the range from 0.51 to 1.69 with an average ratio around 1.010.25. Based on the analysis of the results, it is interesting to note that the activated PKG seems to affect the phosphorylation of proteins associated with the inhibition of cell migration and proliferation, redistribution of actin-associated proteins, and the increase of protein synthesis in late-gestation uteri.
The last topic (chapter5) presents a systematic approach to identify substrates of cyclic-nucleotide dependent protein kinases included PKA and PKG in rat uteri. In vitro kinase assay was performed for strong anion exchange (SAX) fractionated, exogenous phosphatase treated protein mixture to find out possible substrates of kinases as well as their phosphorylation sites. Without the use of radioisotope (32P), which is not accessible for most labs due to safety issue, dozens of potentials substrates can be identified. Those candidates were quantitatively analyzed in vivo upon the treatment of kinase activator. Heat shock protein 27 and filamin A, an 280kDa actin binding protein were known to be substrates of PKA at specific sites. Both of them were found to be phosphorylated in vitro by PKA and have increased phosphorylation upon the treatment of 8-Br-cAMP in vivo, suggesting the integrated strategy here is useful for global exploration of kinase substrates. The knowledge obtained provides critical information to explain physiological insight and cellular processes.
論文目次 Abstract I
中文摘要 III
Acknowledgement V
Tables of Contents VI
List of Tables IX
List of Figures X
Abbreviation XIII
Text 1
自述 160
Chapter 1 Introduction to Mass spectrometry based phosphoproteomics 1
1.1. Proteomics and protein phosphorylation 2
1.2. Mass spectrometry 3
1.3. Strategies for phosphoproteins/phosphopeptides enrichment 4
1.4. MS strategies for phosphopeptide detection 6
1.5. Immobilized metal affinity chromatography (IMAC) 7
1.6. Dimethyl labeling for comparative proteomics 8
1.7. NO/cGMP/PKG relaxation pathway in smooth muscle cells 9
1.8. Reference 11
1.9. Figures and tables 15

Chapter 2 A convenient method to extract MALDI spectra from high-salt buffer containing samples 24
Abstract 25
Introduction 26
Experimental part 28
Result and discussion 30
Extraction of peptide signals from phosphate buffer 30
Elimination of sodium adduct 31
Conclusion 33
Reference 34
Figures 35

Chapter 3 Two-step immobilized metal affinity chromatography (IMAC) for phosphoprotein identification using mass spectrometry 38
Abstract 39
Introduction 40
Experimental part 43
Result and discussion 47
Phospho-affinity of IMAC at protein level 47
Two-step IMAC for the enrichment of phosphopeptides 48
The matrix effect on two-step IMAC 50
Analysis of rat uteri using two step IMAC approach 51
Overview of protein IMAC based approaches in 2005-2006 51
Conclusion 54
Reference 55
Figures and tables 58

Chapter 4 Quantitation of protein phosphorylation in pregnant rat uteri using stable isotope dimethyl labeling coupled with IMAC 69
Abstract 70
Introduction 71
Experimental part 75
Result and discussion 80
IMAC selection of labeled phosphopeptides 80
Quantitation of dimethyl labeled phosphopeptides 81
Peptide sequencing for dimethyl-labeled phosphopeptides 82
Analysis of phosphoproteins in late-gestation rat uteri 83
Biological implications for cGMP activated protein phosphorylation in late gestation rat uteri 84
Conclusion 88
Reference 89
Figures and tables 93

Chapter 5 A systematic proteomics approach for identifying substrates of PKA and PKG 109
Abstract 110
Introduction 111
Experimental part 114
Result and discussion 119
Experimental design 119
Blank test 119
Substrates identification and method specificity 120
Identification of substrates of PKA and PKG 121
Conclusion 125
Reference 126
Figures and tables 129

Chapter 6 Conclusion and Perspective 141
Overview of this study 142
Perspective -- phosphoprotein identification 143
Perspective -- bioinformatics for proteomic research 144
Perspective -- other than global analysis 145

Appendix 149
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