人類叉形頭轉錄因子FOXO3與核酸複合體之結構分析與研究
摘 要
FOXO3a 是屬於FOXO轉錄因子家庭的一員。FOXO蛋白質參與許多訊息傳遞路徑，而且它們的轉錄活性是由許多後修飾機制來調控，包括磷酸化 (phosphorylation)，乙醯化 (acetylation) 與泛素化 (ubiquitination)。因為這三種後修飾作用位置位於FOXO 轉路因子的核酸結合區域的C端，因此這三種後修飾作用可能可以改變與核酸作用的活性。為了要瞭解FOXO如何被調控，我們解出了解析度為2.7Å 的FOXO3a的核酸結合區域與13鹼基對含有FOXO專屬結合區域的核酸複合體的結構。根據位於C端的特殊結構特徵與生化和突變的探討，我們的結果可能可以解釋由磷酸化酶所引起的磷酸化和由以乙醯化酶所作用的乙醯化可以減弱與核酸結合的活性，因此減低FOXO的轉錄活性。另外我們證明一些胸腺嘧啶的甲基對於與FOXO3a的核酸結合區域的辨認是重要的。







複製解旋酶與解旋酶載體之結構與功能分析研究
摘 要
解旋酶載入因子 (helicase loading factor) 被認為在進行核酸複製時，負責把六套體環狀解旋酶傳送到複製叉 (replication fork)。然而如何將解旋酶傳送到核酸上的機制仍然不是很清楚。在枯草桿菌(Bacillus subtilis)中，蛋白質(DnaI)屬於AAA+ 家庭中的一員且負責將六套體解旋酶(DnaC) 傳送到核酸上。在這邊，我們研究嗜熱菌(Geobacillus kaustophilus) GkDnaC與GkDnaI的交互作用並發現在沒有ATP下，GkDnaI可以和GkDnaC形成以比例為6:6的穩定複合體。表面電漿共振分析(Surface Plasmon Resonance, SPR)指出GkDnaI加速GkDnaC傳送到單股核酸上並促進在有ATP下與核酸形成複合體。另外，GkDnaI的C端區域可以單獨與單股核酸作用而且此作用是可被核甘酸(nucleotides)來調控。我們解出解旋酶(GkDnaC)的晶體結構。發現此結構呈現出六套體解旋酶的構造，並在六套體中心形成一個通道. 我們也解出GkDnaI的C端區域與ADP的複合體的2.5Å的晶體結構。此結構除了呈現ADP與Walker A和Walker B 的作用關係，並且指出一個可能與單股核酸作用的帶正電區域。這些發現提供一些資訊對於瞭解解旋酶如何傳送到核酸上有重大助益。

Structural study of human forkhead transcriptional factor FOXO3a
bound to DNA
Abstract
FOXO3a is a transcription factor of the FOXO family. The FOXO proteins participate in multiple signaling pathways, and their transcriptional activity is regulated by several post-translational mechanisms, including phosphorylation, acetylation, and ubiquitination. Because these post-translational modification sites are located at the C-terminal basic region of the FOXO DNA-binding domain, it is possible that these post-translational modifications could alter the DNA-binding characteristics. To understand how FOXO-mediated transcriptional activity, we reported here the 2.7 Å crystal structure of the DNA-binding domain of FOXO3a (FOXO3a-DBD) bound to a 13-bp DNA duplex containing a FOXO consensus binding sequence (GTAAACA). Based on a unique structural feature in the C-terminal region and results from biochemical and mutational studies, our studies may explain how FOXO-DBD C-terminal phosphorylation by protein kinase B (PKB) or acetylation by cAMP-response element binding protein (CBP) can attenuate the DNA-binding activity and thereby reduce transcriptional activity of FOXO proteins. In addition, we demonstrate that the methyl groups of specific thymine bases within the consensus sequence are important for FOXO3a-DBD recognition of the consensus binding site.




Structural and functional studies of replicative helicase and helicase loader
Abstract
Helicase loading factors are thought to transfer the hexameric ring-shaped helicases onto the replication fork during DNA replication. However, the mechanism of helicase transfer onto DNA remains unclear. In Bacillus subtilis, the protein DnaI, which belongs to the AAA+ family of ATPases, is responsible for delivering the hexameric helicase DnaC onto DNA. Here we investigated the interaction between DnaC and DnaI from Geobacillus kaustophilus HTA426 (GkDnaC and GkDnaI) and determined that GkDnaI forms a stable complex with GkDnaC with an apparent stoichiometry of GkDnaC6-GkDnaI6 in the absence of ATP. Surface plasmon resonance analysis indicated that GkDnaI facilitates loading of GkDnaC onto single-stranded DNA (ssDNA) and supports complex formation with ssDNA in the presence of ATP. Additionally, the GkDnaI C-terminal AAA+ domain alone could bind ssDNA, and binding was modulated by nucleotides. We determined the crystal structure of GkDnaC and found that the GkDnaC proteins form a hexamer with a channel in the center. We also determined the crystal structure of the C-terminal AAA+ domain of GkDnaI in complex with ADP at 2.5 Å resolution. The structure not only delineates the binding of ADP in the expected Walker A and B motifs but also reveals a positively charged region that may be involved in ssDNA binding. These findings provide insight into the mechanism of replicative helicase loading onto ssDNA.

Contents
Abstract in Chinese…………………………………………….………............II
Abstract …………………………………………………..................................III
Abbreviations………………………………………………………………………..IV

Part I. Structural study of human forkhead transcriptional factor
FOXO3a bound to DNA
Chapter 1. Introduction……………………………………………………….... ..1
Chapter 2. Materials and Methods
2.1 Expression and purification of FOXO3a-DBD…………………………….... …4
2.2 Crystallization of protein-DNA complex…………………………….….….…. .4
2.3 Data collection and structure determination………………………….….….. ....5
2.4 Electrophoretic mobility shift assay……………………………………....….. ...6
2.5 Fluorescence anisotropy assay………………………………………………. …6
2.6 Steady-state fluorescence measurements……………………………………. …7

Chapter 3. Results
3.1 Overview of the complex structure……………………………………….…. …8
3.2 Major groove recognition within the consensus binding site…………….…. ….9
3.3 The FOXO3a-DBD C terminus forms a coil to interact with the DNA
major groove……………………………………………………………...….… 9
3.4 Interaction between wing 1 and DNA……………………………….……...... .11
3.5 Structural comparison with other FOX proteins………………………...….… .11
3.6 DNA conformation in the FOXO3a-DBD/DNA complex……………...….… .13
3.7 Mutational analyses of FOXO3a-DBD1…………………………………....... .13
3.8 FOXO protein recognizes an AT-rich consensus sequence……………….. .…16
3.9 The C-terminal coil of FOXO3a-DBD was stabilized in the presence of DNA………………………………………..………………………….…....… 16
Chapter 4. Discussion……………………………………………………..… 18
Chapter 5. Conclusion…………………………………………………… .…22
Part II. Structural and functional studies of replicative helicase and
helicase loader
Chapter 1. Introduction…………………………………………………… ……23
Chapter 2. Materials and Methods
2.1 Cloning of helicase and helicase loader ………………..…………………..… 26
2.2 Mutagenesis……………………………………………………………….... …27
2.3 Expression and purification……………………………………………...… .…27
2.4 Gel filtration chromatography………………………………………..……. .…29
2.5 GST pulldown assays……………………………………………………….… 29
2.6 Surface plasmon resonance……………………………………………….... …29
2.7 Crystallization, data collection and structure determination of GkDnaC…. .…31
2.8 Crystallization, data collection and structure determination of GkDnaIC… .….32
2.9 Sample preparation, data collection, and model reconstruction by electron microscopy of GkDnaC/GkDnaI …………………………………………... …33
Chapter 3. Results
3.1 Characterization of GkDnaI……………………………………………….….. .35
3.2 The GkDnaC helicase and GkDnaI form a stable complex in the absence of nucleotides………………………………………………………………….. …35
3.3 Stoichiometry of the GkDnaC/GkDnaI complex…………………………… …37
3.4 GkDnaI facilitates ssDNA binding when in complex with GkDnaC……….….37
3.5 The C-terminal domain of GkDnaI binds ssDNA………………………….…..39
3.6 Structure of the GkDnaC………………………………………………….…....39
3.7 Structure of the C-terminal AAA+ domain of GkDnaI…………………..….…41
3.8 Nucleotide binding site in GkDnaIC………………………………………...….42
3.9 Structural comparison of GkDnaIC with other helicase loader AAA+ ATPase domains…………………………………………………………………….….. 43
3.10 The potential GkDnaIC ssDNA binding region………………………….....…44
3.11 Preliminary EM analysis of GkDnaC/GkDnaI complex ……………………..46
Chapter 4. Discussion …………………………………………………..........… 48
Chapter 5. Conclusion…………………………………………………..…....…52
Figures and Tables………………………………………………………..…….… 53
References…………..……………………………………………………...… 89

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