對生物膜具活性的胜肽誘導相分離脂質膜產生結構上擾動

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許文瑋(Wen-Wei Hsu) 查詢紙本館藏

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化學工程與材料工程學系

論文名稱

對生物膜具活性的胜肽誘導相分離脂質膜產生結構上擾動
(STRUCTURAL DISRUPTION ON THE PHASE-SEPARATED LIPID MEMBRANES BY MEMBRANE-ACTIVE PEPTIDES)

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摘要(中)

在特定的生物條件下，生物膜表面會因相分離現象的產生而形成不同的結構區域。此結構區塊的產生大大地左右生物膜的物理性質，進而影響具有膜活性的胜肽與生物膜之間的互相作用。最近的研究指出，相分離的現象對具膜活性的胜肽之吸附或插入於生物膜的現象影響甚鉅。然而，此現象背後的作用機制卻依然未知。為了釐清這未知的機制，我們使用表面壓力測量、X射線繞射技術和螢光滲透測定等技術，研究相分離如何調節脂質膜的物理性質以及調控蜂毒肽和澱粉樣蛋白(Aβ)的膜穿孔能力；近期的研究發現，澱粉樣蛋白(Aβ)的膜活性，特別是澱粉樣蛋白(Aβ)的膜穿孔能力，可能與阿茲海默症的發病機制高度相關。我們的研究結果發現，蜂毒肽的膜穿孔能力高度取決於脂質膜的相分離狀態，其中液態無序相的存在為蜂毒肽膜穿孔的必要條件。令我們驚訝的是，無論脂質膜的相態為何，任何聚集狀態下的澱粉樣蛋白(Aβ)都無法於脂質膜上形成孔洞或在其結構上造成明顯的破壞。基於此一觀察，我們探討了脂質膜之物理性質(如：脂質分子排列的緊密度)對於具膜活性胜肽與生物膜之間交互作用的影響，並且討論其生物上的相關性。

摘要(英)

Membrane phase separation is a phenomenon wherein the lipid constituents of a membrane segregate discriminately to form distinct in-plane domains (or phases) upon certain biologically relevant conditions and greatly dictates the physical properties of a membrane, which govern the interactions between biomembranes and the membrane-active peptides. Recent studies have reported how the phase separation could affect the binding and insertion of membrane-active peptides to membranes. Nevertheless, the general mechanisms underlying the correlations remain elusive. To contribute to the exploration of the general mechanisms, we employ the surface pressure measurements, X-ray scattering techniques, and fluorescent leakage assays to investigate how the phase separation and associated phase behavior modulate the physical properties of a lipid membrane and how the modulations in turn affect the membrane perforation capability of two membrane-active peptides, melittin and amyloid beta (Aβ); the membrane-active aspects, particularly the membrane perforation capability, of Aβ have drawn extensive scrutiny very recently, due to their potential involvement in the pathogenesis of Alzheimer’s disease. It is found that while the membrane perforation capability of melittin was highly dependent on the phase condition of a membrane, with the presence of the liquid-disordered phase being essential and the emergence of phase boundaries being positively influential, to our surprise, no pore formation or other structural disruptions on membranes could be ascribed to Aβ of any aggregation state, regardless of the phase condition of a membrane. The physical principles underlying the observations are explored in the context of the molecular packing densities of a membrane, and the biological implications are also discussed

關鍵字(中)

★ 具膜活性胜肽
★ 澱粉肽
★ 蜂毒肽
★ 相分離脂質膜
★ 螢光洩漏
★ 分子單層槽

關鍵字(英)

★ membrane-active peptide
★ amyloid beta
★ melittin
★ phase-separated membrane
★ fluorescence leakage
★ Langmuir trough

論文目次

摘要 I
Abstracts II
致謝 III
Table of Contents VI
List of Figure IX
List of Table XI
List of Equaiton XII
Chapter 1 Introudction 1
1-1. Membrane-active Peptide 1
1-2. Alzheimer’s Disease and Amyloid Beta 4
1-2-1. Alzheimer’s disease 4
1-2-2. Amyloid precursor protein (APP) 6
1-2-3. Amyloid beta peptide 8
1-2-4. The correlation between Aβ and lipid rafts 12
1-3. Cell Membrane and Artificial Lipid Membrane 14
1-3-1. Lipid and cholesterol 14
1-3-2. Cell membrane 17
1-3-3. Artificial membrane 18
1-4. Lipid Raft and Phase Separation 20
1-4-1. Lipid raft 20
1-4-2. Phase separation and phase diagram 23
1-5. Motivation 28
Chapter 2 Materials and Experimental Method 30
2-1. Materials 30
2-1-1. Lipid 30
2-1-2. Peptide 33
2-1-3. Fluorescence dye 36
2-1-4. Non-biomaterials 37
2-2. Sample Preparation 38
2-2-1. Amyloid beta (Aβ) preparation 38
2-2-2. Vesicle preparation 41
2-3. Experimental Method 42
2-3-1. Langmuir trough 42
2-3-2. Fluorescence assay 49
2-3-3. Dynamic light scattering 53
2-3-4. Ultraviolet-visible spectroscopy 54
2-3-5. Circular dichroism 56
Chapter 3 Result 58
3-1. Size of the Vesicles 58
3-2. The Aggregation State of Aβ 59
3-3. Peptide-Induced Content Leakage of Phase-separated Vesicles 62
3-3-1. Melittin 62
3-3-2. Amyloid beta (Aβ) 77
3-4. The Π-A Isotherm 79
3-4-1. Single-component monolayers 79
3-4-2. Multi-component monolayers 82
3-5. The Compressibility Modulus of Phase-separated Membrane 87
3-5-1. The compressibility modulus of DPPC, DOPC, and cholesterol 87
3-5-2. The compressibility modulus of DPPC/DOPC/Chol mixture 89
3-6. Peptide Adsorption in Lipid Monolayer 93
Chapter 4 Discussion 95
4-1. The Correlation between Peptide and Phase-separated Membrane 95
4-2. The Physical Property Affects the Extent of Membrane Disruption 100
4-3. Amyloid Beta Disrupts the Phase-separated Membrane or not 102
4-4. The Mechanism of Disruption in Phase-separated Membrane by Melittin 107
Chapter 5 Conculsion 109
Reference 110
Appendix 117

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指導教授

陳儀帆(Yi-Fan Chen)

審核日期

2017-8-4

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