The Myopathy-Causing Mutation in αB-crystallin Alters Its Interaction with Desmin Intermediate Filament

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研究生：	李皙哲 Lee, Hsi-Che
論文名稱：	The Myopathy-Causing Mutation in αB-crystallin Alters Its Interaction with Desmin Intermediate Filament 造成肌病變的αB-水晶體突變蛋白改變與肌間線蛋白形成的中間絲的交互作用
指導教授：	彭明德 Perng, Ming-Der
口試委員:	張壯榮李文權
學位類別：	碩士 Master
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2011
畢業學年度：	100
語文別：	英文
論文頁數：	76
中文關鍵詞：	肌間線蛋白、與肌間線蛋白有關的肌病變、中間型絲、小分子熱休克蛋白、磷酸化、αB-水晶體蛋白、突變
外文關鍵詞：	Desmin, Desmin-related myopathy, Intermediate filament, Small heat shock protein, Phosphorylation, αB-crystallin, Mutation
相關次數：	點閱：2 下載：0
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小型熱休克蛋白：αB水晶體蛋白的突變是造成多種疾病的原因，例如：擴張型心肌病變、肌間線蛋白肌病變，以及先天性的白內障。其中，肌間線蛋白肌病變最早被發現其致病因素直接和肌間線蛋白的突變有關，此突變蛋白不僅改變了本身蛋白質的結構更牽連與它有密切結合關係的蛋白質，進而造成電子密度高的顆粒纖維狀物質的形成。此疾病與中間絲蛋白的細胞骨架瓦解有絕對的相關,由此可知小型熱休克蛋白對於中間絲蛋白具有重要的生理意義。小型熱休克蛋白被認為扮演一個伴隨蛋白的角色，可以和不正常折疊的蛋白質結合並避免形成不正常的蛋白質結構，進而讓細胞遠離逆境壓力。一個位於αB水晶體蛋白上的第154個胺基酸上的誤義突變：由甘胺酸突變成絲胺酸，最近被檢驗出此突變和晚發性的末梢液泡肌病變有關，而與一些典型的心肌病變或是呼吸缺陷還有白內障這些疾病無關。此一突變位於哺乳動物高度保留性的αB水晶體蛋白基因序列中，並更早就被發現於一個罹患單純心肌症的病人檢體中。這項研究藉由生物化學以及分子與細胞生物的方式去探討G154S-αB水晶體蛋白對於肌間線蛋白的交互作用的能力是否因為突變而造成改變。共沉降實驗分析顯示出G154S-αB水晶體蛋白增加了與肌間線蛋白結合的能力。利用穿透式電子顯微鏡觀察此兩種蛋白質的交互作用，也的確出現了G154S-αB水晶體蛋白的顆粒蛋白攀附在肌間線蛋白所形成的中間絲纖維上的現象。而在短暫型DNA轉染細胞系統的研究項目中，實驗數據顯示G154S-αB水晶體蛋白並不會因為突變了而影響它在人類乳癌細胞、老鼠肌原母細胞、以及倉鼠腎細胞裡的分佈，但是在C2C12的細胞比起正常的水晶體蛋白會降低了些微的溶解度。R120G-水晶體蛋白被指出同樣也會造成肌間線蛋白肌病變，藉此可對照R120G-水晶體蛋白在短暫型DNA 轉染細胞系統所引起的，明顯地促進與肌間線蛋白的結合能力、蛋白質溶解度的改變，以及導致形成細胞內不正常蛋白堆積物。另一方面，在R120G-水晶體蛋白和G154S-水晶體蛋白的第59號的絲胺酸上都出現了特殊地磷酸化的現象。綜合以上的研究結果，G154S-水晶體蛋白的致病機制可能與導致肌間線蛋白肌病變的R120G-水晶體蛋白不盡相同。

Mutations in the small heat shock protein (sHSP) αB-crystallins cause a range of human diseases including dilated cardiomyopathy (DCM), desmin-related myopathy (DRM) and congenital cataracts. DRM was the first discovered associated with desmin mutations which can affect themselves and closely interacted proteins that typically tending to incomplete assembly of desmin and formation of electro-dense granulofilamentous materials. These diseases involve the disruption of the intermediate filament (IF) cytoskeleton and thus identified intermediate filaments as important physiological targets of sHSPs. Recently, a missense mutation Gly154Ser (G154S) in αB-crystallin was reported to be associated with a late-onset distal vacuolar myopathy without cardiac or respiratory dysfunction and cataracts. This mutation affects a highly conserved amino acid residue among the αB-crystallin in mammals and has been identified earlier in patients with isolated cardiomyopathy. In this study, the effects of G154S mutation on αB-crystallin’s ability to interact with desmin IFs was investigated in details using a combination of biochemical, molecular and cell biological approaches. Cosedimentation assay showed that the G154S mutation increased the binding of αB-crystallin to assembled desmin IFs. Transmission electron microscopy confirmed that the G154S αB-crystallin particles decorated the assembled desmin filaments. Transient transfection studies revealed that the expression of G154S αB-crystallin did not affect its distribution but accomplishment of slightly decreased of solubility in C2C12 cell fraction study compared to the wild type αB-crystallin. This is in contrast to the R120G mutation reported in desmin-related myopathy, where this mutation affected the solubility of αB-crystallin and promoted its interaction with desmin filament leading to intracellular aggregates formation in transiently transfected cells. When transfected into a range of cell lines, both R120G and G154S αB-crystallin mutants, but not the wild type protein, increased the phosphorylation of αB-crystallin at Ser59 site. Taken together, these data suggest that the G154S mutation may be involved in the pathogenesis of myopathy through a mechanism that is different from the R120G mutation found in DRM.

Contents    I
Abstract    V
中文摘要    VI
致謝    VII
Abbreviation    VIII
Chapter 1：Introduction    9
1.1 Intermediate filaments    9
1.2 Desmin and DRM    3
1.3 The small heat shock proteins and αB-crystallin    5
1.4 Interaction of αB-crystallin with cytoskeletal proteins    6
1.5 Actin-based microfilaments and microtubules    6
1.6 Intermediate filaments    7
1.7 Human diseases associated with αB-crystallin mutations    9
1.8 Molecular pathogenesis of DRM    11
1.9 In vitro studies    11
1.10 Animal models    12
1.11 Eliminating the aggregates    13
Chapter 2：Material and Methods    15
2.1 Construction of expression plasmids    15
2.2 Construction of G154S αB-crystallin by site directed mutagenesis    15
2.3 Preparation of competent cells    17
2.4 Expression and purification of recombinant αB-crystallin    17
2.5 Purification of G154S αB-crystallin by column chromatography    18
2.6 Determination of protein concentration    19
2.7 Intermediate filament assembly in vitro    19
2.8 Cosedimentation assay    20
2.9 Transmission electron microscopy    20
2.10 Cell culture and transient transfection    21
2.11 Generation of stable cell lines    21
2.12 Immunofluorescence microscopy    22
2.13 Cellular fractionation    23
2.14 Preparation of cytoskeletal fractions    24
2.15 Immunoprecipitation    24
2.16 Immunoblotting    25
2.17 Silver staining    26
Chapter 3：Results    27
3.1 The effect of G154S αB-crystallin on the interaction with desmin filaments in vitro.    27
3.1.1 Expression and purification of recombinant G154S αB-crystallin.    27
3.1.2 Interaction of αB-crystallin and desmin filaments in vitro.    28
3.1.3 Visualization of the interaction between αB-crystallin and desmin by electron microscopy.    29
3.2 The effect of αB-crystallin mutation on the IF networks in cultured cells determining.    30
3.2.1 Expression level and solubility property of αB-crystallin    31
3.2.2 Expression of αB-crystallin in C2C12 cells.    32
3.3 Generation of stable cell lines.    36
3.3.1 Screening of BHK21 cell lines expressing αB-crystallin.    37
3.3.2 Screening of C2C12 cell lines expressing αB-crystallin.    38
Chapter 4：Disscussion    40
4.1 Interaction between desmin and αB-crystallin.    40
4.2 Establishment of stable cell line.    41
4.3 The event which transfected αB-crystallin into cell model related to late onset disease of DRM.    41
Appendix    43
Appendix 1. IFs are classified into five major families.    43
Appendix 2. Model of IF assembly    44
Appendix 3. Draw of desmin mutations    45
Figures    46
Figure 1-1. Electrophoretic analysis of expression and purification of G154S αB-crystallin.    46
Figure 1-2. Purification of G154S αB-crystallin by anion exchange chromatography.    47
Figure 1-3. Purification of G154S αB-crystallin by gel filtration chromatography.    48
Figure 1-4. Protein concentration determination.    49
Cosedimentation assay explained    50
Figure 1-5.Cosedimentation of WT αB-crystallin with wild-type desmin in vitro.    51
Figure 1-6. G154S αB-crystallin cosediment with wild-type desmin filament.    52
Figure 1-7. Visulization of WT and G154S αB-crystallin binding to desmin intermediate filaments in vitro by electron microscopy.    53
Figure 2-1. Formation of cytoplasmic aggregates in BHK21 cells expressing mutant αB-crystallin.    54
Figure 2-2. Analysis of wild type and mutant αB-crystallin in transiently transfected BHK21 cells by immunoblotting.    55
Figure 2-3. Effect of C2C12 cells transiently transfected with either wild type αB-crystallin (A), or R120G αB-crystallin (B), or G154S αB-crystallin (C) after 48 hours.    56
Figure 2-4. Distribution of WT and mutant αB-crystallin in relation to the endogenous desmin IF networks.    57
Figure 2-5. Wild-type and mutant αB-crystallin were transiently transfected into C2C12 cells.    58
Figure 2-6. Immunoblotting analysis of wild type and mutant αB-crystallin expressed in MCF7 cells.    59
Figure 2-7. Effect of αB-crystallin mutations upon mitochondrial distribution in C2C12 cells.    60
Figure 2-8. The problems and improvements in co-immunoprecipitation.    61
Figure 2-9. Co-immunoprecipitation of NT, WT, R120G, and G154S αB-crystallin in C2C12 cells.    62
Figure 3-1. Killing curve of BHK21 cells treated with G418 and hygromycin.    63
Figure 3-2. Stable clones were selected from single cell in each 96 well petri dish.    64
Figure 3-3. Expression level of αB-crystallin in selected BHK21 stable clones.    65
Figure 3-4. Cytoskeletal preparation was analyzed by coomassie blue staining and silver staining.    66
Figure 3-5. Expression level of R120G αB-crystallin stable clones.    67
Figure 3-6. R120G αB-crystallin was examined by immunofluorecent microscopy.    68
Figure 3-7. C2C12 stable clone selection of cells expressed transfected αB-crystallin.    69
References    70

                                

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