博碩士論文 101233005 詳細資訊




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姓名 林均穆(Jun-mu Lin)  查詢紙本館藏   畢業系所 系統生物與生物資訊研究所
論文名稱 利用大腸桿菌蛋白質體晶片找出與2-氧基組胺酸交互作用之蛋白質
(Identification of 2-oxohistidine interacting proteins using E. coli proteome chips)
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摘要(中) 在細胞呼吸作用下,活性氧化物不斷地產生,而細胞內的蛋白質也同時遭受到活性氧化物的破壞。由於組胺酸在其強金屬螯合的能力下,組胺酸容易受到銅離子、鐵離子以及過氧化氫的金屬催化氧化作用,造成其容易被氧化成2-氧基組胺酸。我們假設生物會演化出抗氧化能力來對抗這種2-氧基組胺酸的產生,因此,在細胞內會有蛋白質可以辨認這樣的氧化官能基(2-氧基組胺酸)。我們利用兩條人造且含有2-氧基組胺酸的肽鏈,以及含有大於五千種蛋白質的大腸桿菌蛋白質體晶片,我們篩選出十個會與2-氧基組胺酸產生交互作用的蛋白質,並且利用偏極化螢光試驗和第三條含有2-氧基組胺酸的肽鏈驗證其交互作用的能力,最後我們測量了各個蛋白質與2-氧基組胺酸之間的親和力。我們利用生物資訊的方式在這十個蛋白質內找出一段共有結合序列,此序列也被發現在人類蛋白質S100A1上,而S100A1也利用上述的方式成功的驗證其具有與2-氧基組胺酸產生交互作用的能力,而這一發現說明了辨認2-氧基組胺酸這樣的修飾在演化上是具有共通性的。我們結合了人造肽鏈與蛋白質體晶片,建立一個有效且高敏感度的研究平台,可提供轉譯後修飾更進一步的研究,即使是小到只有一個氧基的轉譯後修飾。
摘要(英) Cellular proteins are constantly damaged by reactive oxygen species generated by cellular respiration. Due to its metal-chelating property, histidine residues are easily oxidized in the presence of Cu/Fe ions and H2O2 via metal-catalyzed oxidation, usually converted to 2-oxohistidine. We hypothesize that cells may have evolved antioxidant defenses against the generation of 2-oxohistidine residues on proteins, and therefore there would be cellular proteins which specifically interact with this oxidized side chain. Using two chemically synthesized peptide probes containing 2-oxohistidine, high-throughput interactome screening was conducted using the E. coli K12 proteome microarray containing >5000 proteins. The 10 interacting proteins were successfully validated using fluorescence polarization assay, a third peptide probe of different sequence, as well as binding constant measurements. A consensus binding motif was identified among these 10 bacterial interacting proteins based on bioinformatic prediction, which also appeared to be present on human S100A1 protein. The preferential binding of S100A1 with 2-oxohistidine over histidine was successfully validated using all three peptide probes, suggesting that the capacity to recognize 2-oxohistidine modification may be evolutionarily conserved from bacteria to humans. The combination of chemically engineered peptide probes with proteome microarrays proves to be an efficient discovery platform for protein interactomes of unusual post-translational modifications, sensitive enough to detect even the insertion of a single oxygen atom in this case.
關鍵字(中) ★ 大腸桿菌蛋白質體晶片
★ 二氧基組胺酸
★ 胜肽與蛋白質交互作用
★ 轉譯後修飾
★ 氧化
★ 人類S100A1蛋白質
關鍵字(英) ★ E. coli proteome chip
★ 2-oxohistidine
★ Peptide-protein interaction
★ Post-translational modification
★ Oxidation
★ Human S100A1 protein
論文目次 中文摘要 i
ABSTRACT ii
ABBREVIATIONS iv
ACKNOWLEDGMENTS v
TABLE OF CONTENTS vi
LIST OF FIGURES ix
LIST OF TABLES xi
I. Introduction 1
II. Experimental Procedures 4
II.1 Fabrication of E. coli K12 proteome chip 4
II.2 Oxidation of peptide histidine residue 4
II.3 Labeling fluorescent dyes on peptides 5
II.3.1 Control peptide probe with DyLightTM 650 (AG peptide and SE peptide) 5
II.3.2 Control probe with DyLightTM 550 (IA peptide) 6
II.3.3 Positive probe with DyLightTM 550 (Oxo-AG peptide and Oxo-SE peptide) 6
II.3.4 Positive probe with DyLightTM 650 (Oxo-IA peptide) 7
II.4 E. coli K12 proteome chip assays with 2-oxohistidine peptides 7
II.5 Heat Map 9
II.6 Functional interaction analysis 9
II.7 Fluorescence polarization assay 10
II.8 Measurement of dissociation constant (Kd) 10
II.9 Motif Search with GLAM2 11
II.10 Protein 3D structure and secondary structure prediction 12
III. Results 13
III.1 Oxidation of peptide histidine residue 16
III.2 E. coli K12 proteome chip assays 18
III.3 Functional interaction analysis 28
III.4 Fluorescence polarization assays 33
III.5 Measurement of binding affinity 36
III.6 Motif Searching in E. coli proteome and human proteome 42
III.7 Kd measurement between human S100A1 protein and the oxidative peptides 48
IV. Discussion 50
V. References 56
VI. Supplementary Information 70
VI.1 Supplementary Information Tables 70
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指導教授 陳健生 審核日期 2016-1-21
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