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系統識別號 U0026-2005201115310200
論文名稱(中文) FOXP1與Myocyte Nuclear Factor的DNA Binding Domains之結構動力學與功能間的關係
論文名稱(英文) Structure-Dynamics-Function Relationships of the DNA Binding Domains of FOXP1 and Myocyte Nuclear Factor
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 99
學期 2
出版年 100
研究生(中文) 朱苑萍
研究生(英文) Yuan-Ping Chu
學號 s5891116
學位類別 博士
語文別 英文
論文頁數 165頁
口試委員 指導教授-莊偉哲
口試委員-陳金榜
口試委員-蕭傳鐙
口試委員-賴明德
口試委員-張文粲
召集委員-黃溫雅
中文關鍵字 結構  動力學  DNA結合蛋白 
英文關鍵字 NMR backbone dynamics  winged-helix/forkhead protein  domain swapping 
學科別分類
中文摘要 Forkhead box (FOX) proteins為一轉錄因子家族,對於調控參與細胞生長、增生、分化和長壽基因的表現扮演著重要的角色。Forkhead domain為一包含有80-100個胺基酸的DNA binding motif,由於其蛋白質構形上具有兩個loop結構,使其外表看似蝴蝶,所以又稱之為winged-helix domain。為了研究Forkhead domain之結構功能和動力學之間的關係,我利用NMR光譜探討FOXP1和myocyte nuclear factor (MNF)的Forkhead domains。FOXP1屬於Forkhead轉錄因子中的P-subfamily。根據size-exclusion chromatography分析指出FOXP1的Forkhead domain存在monomer與dimer的混合物。FOXP1之Forkhead domain及C61S與C61Y的突變株之dissociation constants各別為27.3、28.8和332.0 M。相對的,FOXP1 A39P之突變株僅形成單體。NMR分析結果也顯示FOXP1 C61S和C61Y突變株存在兩種構形。FOXP1 A39P/C61Y之水溶液結構近似於FOXP2單體之X-ray結晶結構。FOXP1 A39P/C61Y和C61Y突變株之骨架動力學的比較顯示FOXP1的monomer中位在Hinge region上靠近helix 3的胺基酸存在最大之構形變遷。此外,FOXP1的dimer上A39擁有較低的order parameter,顯示具有ps-ns timescale的internal motion。以上結果指出FOXP1上Hinge region的動力學狀態對於swapped dimer的形成相當重要。動力學分析亦顯示位於FOXP1上DNA結合表面的胺基酸同時存在ps-ns與s-ms timescales的運動,指出FOXP1與DNA的結合具有高度的動態變化。Myocyte nuclear factor (MNFs)轉錄因子選擇性表現在雞肉幹細胞。本研究中我們提出MNF之DNA binding domain的立體結構,且結構分析顯示其為winged helix family的一員。MNF存在與DNA結合的高親和性,具有2.57 nM的解離常數。MNF與DNA結合之後,DNA recognition helix之前、H2-H3 loop和wing 1存在最大的化學位移變動。動力學分析顯示N-和C-端與wing 1區域為變動最大的區域。C-端為DNA結合後NOE變化最大區域,同時與DNA結合之後大部分的區域皆變得較為固定。有趣的是,H2上的胺基酸、DNA recognition helix和wing 1區域於結合DNA之後存在conformational exchange。MNF上H2-H3 loop中的非DNA結合之胺基酸同時存在s/ms與ps/ns time scales的運動,在與DNA結合之後,快速與慢速運動皆下降。膠體滯留分析也顯示H2-H3 loop上K35、R41和G46的突變存在1.7、2.1和3.5倍的DNA結合力下降,顯示這些胺基酸對於DNA結合是重要的。這些結果顯示MNF對DNA的結合可能受到非DNA作用胺基酸之動力學調節。本研究對於FOX proteins如何形成domain swapping及與DNA結合可能受到其較不具保留性區域之動力學特性提供新的解析。
英文摘要 Forkhead box (FOX) proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. The forkhead domain, a DNA-binding motif containing 80-100 amino acid residues, is also known as the winged-helix domain due to the butterfly-like appearance of the loops in the protein structure. To study structure-function-dynamics relationships of the forkhead domain, I used NMR spectroscopy to study the forkhead domains of FOXP1 and myocyte nuclear factor (MNF). FOXP1 belongs to the P-subfamily of forkhead transcription factors. According to size exclusion chromatography analysis, the forkhead domain of FOXP1 existed as a mixture of monomer and dimer. The dissociation constants of the forkhead domain of wild-type, C61S and C61Y mutants of FOXP1 were 27.3, 28.8, and 332.0 M, respectively. In contrast, FOXP1 A39P mutant formed only a monomer. NMR analysis also showed that FOXP1 C61S and C61Y mutants existed as a mixture. The solution structure of FOXP1 A39P/C61Y mutant was similar to the X-ray structure of the FOXP2 monomer. Comparison of backbone dynamics of FOXP1 A39P/C61Y and C61Y mutants showed that the residues preceding helix 3, the hinge region, exhibited the largest conformational exchange in FOXP1 monomer. The A39 residue of FOXP1 dimer has a lower order parameter with internal motion on the ps-ns timescale, suggesting that the dynamics of the hinge region of FOXP1 are important in the formation of the swapped dimer. The analysis also showed that the residues exhibiting the motions on the ps-ns and s-ms timescales were located at the DNA-binding surface of FOXP1, suggesting the interactions between FOXP1 and DNA may be highly dynamic. Myocyte nuclear factors (MNFs) are transcription factors that are selectively expressed in myogenic stem cells. We here reported 3D structure of the DNA-binding domain of MNF that is a member of the winged helix family. MNF exhibited high affinity DNA binding with a dissociation constant of 2.57 nM. The region preceding the DNA-recognition helix, the H2-H3 loop and the wing 1, exhibited highest chemical shift perturbation upon DNA binding. Dynamics analysis showed that the N- and C-termini and the wing 1 region were the most flexible regions. The C-terminal region exhibited highest NOE change, and most of the regions became more rigid upon DNA binding. Interestingly, the residues in H2, DNA recognition helix, and wing 1 region exhibited conformational exchange upon DNA binding. The non-DNA binding residues in the H2-H3 loop of MNF exhibited the motions on both the s/ms and ps/ns time scales, which were reduced upon DNA binding. Gel retardation analysis also showed that the mutations of the residues K35, R41, and G46 in the H2-H3 loop exhibited a 1.7-, 2.1-, and 3.5-fold decrease in binding to DNA, suggesting that they are important for DNA binding. These results showed that the binding of MNF to DNA may be mediated by the dynamics of the non-DNA interacting residues. This study provides a new insight into that how domain swapping and the DNA binding of FOX proteins may be regulated by the dynamical properties of their less conserved regions.
論文目次 中文摘要 i
Abstract ii
Acknowledgments iii
Table of contents iv
List of Tables viii
List of Figures ix
Abbreviations xiii
Instruments xiv
Chapter 1
Introduction
1.1 Winged-helix/forkhead (FOX) transcription factors 1
1.1.1 Disease-related mutations on Fox genes 2
1.2 Structures of the winged helix/forkhead domains 3
1.2.1 Structural difference among the forkhead domains 3
1.2.2 Structural comparison in the DNA-bound forkhead domains 4
1.2.3 The common structural features in the forkhead domains 6
1.3 FOXP subfamily of forkhead transcription factors 9
1.3.1 The crystallographic structure of FOXP2-DNA complex 12
1.5 FOXK subfamily of forkhead transcription factors 13
Chapter 2
Specific aims 16
Chapter 3
Materials and methods
3.1 Gene construction 19
3.1.1 The DNA binding domain of foxp1 gene 19
3.1.2 The DNA binding domain of mnf gene 20
3.2 Protein expression 20
3.2.1 Unlabeled protein preparation 20
3.2.2 2H, 15N, 13C labeled protein preparation 21
3.2.3 Cell extracts 21
3.3 Protein purification 22
3.4 Tricine SDS-PAGE analysis 23
3.5 NMR sample preparation 25
3.5.1 Sample condition for FOXP1 26
3.5.2 Sample condition for MNF 26
3.6 Size-exclusion chromatography analysis 26
3.7 Differential scanning calorimetry (DSC) 27
3.8 Fluorescence measurements 27
3.9 Gel retardation analysis 28
3.10 Nuclear magnetic resonance (NMR) spectroscopy 29
3.10.1 Chemical shift perturbation calculation 29
3.10.2 Structure calculations 30
3.10.3 NMR relaxation measurements 31
3.10.4 The model-free analysis 32
Chapter 4
Results
4.1 FOXP1 and its domain swapping
4.1.1 Protein preparation and characterization 34
4.1.1.1 Gene construction 34
4.1.1.2 Protein expression and purification 35
4.1.2 Buffer conditions tests for NMR sample preparation 36
4.1.3 Size-exclusion chromatography analysis 38
4.1.4 Thermostabilities of FOXP1 wild-type and its mutants 39
4.1.5 The dimer to monomer transition of FOXP1 40
4.1.6 Sequence-specific assignments and secondary structure elements analysis 40
4.1.6.1 Sequential assignments 40
4.1.6.2 Major and minor resonances found from FOXP1 C61S and from C61Y NMR spectra 41
4.1.6.3 Secondary structural determination 42
4.1.6.4 Chemical shift perturbation comparisons 43
4.1.7 FOXP1 forms a domain-swapped homodimer 45
4.1.8 Interaction of the A39P mutant of FOXP1 with DNA 45
4.1.9 Solution structure calculation for FOXP1 A39P/C61Y 46
4.1.10 Structure description for FOXP1 A39P/C61Y 47
4.1.11 Structural comparison of FOXP1 A39P/C61Y with other forkhead domains 49
4.1.12 Relaxation measurements for the monomeric and dimeric FOXP1 51
4.1.13 Model-free analysis of the monomeric and dimeric FOXP1 53
4.1.13.1 The rotational correlation time 53
4.1.13.2 Model-free analysis 54
4.1.14 CPMG delay measurements for the monomeric form of FOXP1 56
4.1.15 Spectral density mapping at multiple fields for the dimeric FOXP1 57
4.2 MNF and its DNA binding
4.2.1 Protein expression and purification of MNF 59
4.2.2 Sequence-specific assignments and secondary structure element analysis 59
4.2.3 The structural comparison between the DNA free and bound MNF 61
4.2.4 Structural comparison with other forkhead domains 63
4.2.5 Backbone dynamics determination of MNF and its DNA complex 64
4.2.6 Dynamics comparison 68
4.2.7 Gel retardation analysis of MNF 69
Chapter 5
Discussion
5.1 FOXP1 and its domain swapping
5.1.1 Monomer-dimer equilibrium of the forkhead domain of FOXP1 71
5.1.2 The structural features for the swapped dimer formation 72
5.1.3 The substantial structural differences among the forkhead domains 74
5.1.4 The correlation of weak DNA binding with FOXP1 75
5.1.5 Hydration effect 76
5.1.6 Backbone dynamics contributes to domain swapping and DNA recognition 76
5.2 MNF and its DNA binding
5.2.1 The correlation of the non-conservative regions with DNA binding 81
5.2.2 Backbone dynamics contributes to DNA recognition 83
5.2.3 The effects of non-conservative regions on DNA binding 85
Chapter 6
Conclusions 88
References 90
Tables 106
Figures 121
Personal information 164
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