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系統識別號 U0026-2501201814323100
論文名稱(中文) 人類肝癌衍生生長因子的PWWP結構區域交換與SMYD1交互作用在基因調控的關連
論文名稱(英文) Domain swapping and SMYD1 interactions with the PWWP domain of human hepatoma-derived growth factor for gene regulation
校院名稱 成功大學
系所名稱(中) 生物科技與產業科學系
系所名稱(英) Department of Biotechnology and Bioindustry Sciences
學年度 106
學期 1
出版年 107
研究生(中文) 陳俐穎
研究生(英文) Li-Ying Chen
學號 L68001010
學位類別 博士
語文別 英文
論文頁數 105頁
口試委員 指導教授-陳俊榮
召集委員-戴明泓
口試委員-王涵青
口試委員-羅玉枝
口試委員-呂佩融
口試委員-伍素瑩
口試委員-翁秉霖
中文關鍵字 人類肝癌衍生生長因子  PWWP 區域  SMYD1 啟動子  結構區域互換 
英文關鍵字 HDGF  PWWP domain  SMYD1  domain swapping 
學科別分類
中文摘要 人類肝癌衍生生長因子(Human hepatoma-derived growth factor)利用其在序列N端具有高度保留性的PWWP區域與染色體結合以及變異性較高的序列C端進行下游基因調控,使之參與不同的細胞過程,如:血管病變,星形膠質細胞增殖以及心血管分化,而過度表現的人類肝癌衍生生長因子與許多種癌症以及心肌不正常發育有著高度的關聯性。本研究希望能探討人類肝癌衍生生長因子與染色體上特殊的啟動子結合前後,其結構上的變化,了解在基因調控方面,人類肝癌衍生生長因子與DNA的交互作用以便未來應用於藥物設計方面。研究中以點突變方式提高了人類衍生生長因子於大腸桿菌表現系統中的表現量,並證明位於序列N端的PWWP區域於DNA與nucleolin的結合扮演重要角色;同時也解析出PWWP區域未與DNA結合以及與SMYD1啟動子結合後的結構。PWWP區域與SMYD1結合後,其結構會由原本單聚體藉由高度擺動性的loop2(hinge loop)形成二聚體並產生結構區域交換現象(3D domain swapping),原來擺動度高的loop2則會變成穩定的α螺旋(αC),並且藉由位於C/N terminus的loop1和4上的Lys19、Gly22、Arg79以及Lys80與10個鹼基對的SMYD1上之小溝(minor groove)結合。本研究解析出第一個PWWP-SMYD1複合體結構並發現與DNA形成複合體後,會造成結構區域交換現象,將其結構與功能性研究結合後,進一步提供人類肝癌衍生生長因子與DNA結合機制的新觀點。
英文摘要 Domain swapping and SMYD1 interactions
with the PWWP domain of
human hepatoma-derived growth factor for gene regulation

Li-Ying Chen
Chun-Jung Chen
Department of Biotechnology and Bioindustry Sciences
College of Bioscience and Biotechnology

SUMMARY

Human Hepatoma-derived growth factor (human HDGF) is highly expressed in the tumour
cell lines and is related to various cancers. The expression yield of HDGF could be increased
by rare codon mutation for E. coli, whereas the stability of HDGF and the PWWP domain
can be optimized by the addition of ligand, protease inhibitor or chelator agent. The apo
PWWP domain contains four β-strands, two α-helices, a flexible loop2, and the conserved
PWWP motif locates on the loop1. The HDGF PWWP domain undergoes domain swapping
to transform its overall conformation from monomeric globular folding into an extended
dimeric structure upon 10-bp SMYD1 (SET-MYND domain) binding dramatically. The
flexible loop2 functions as a hinge loop with the partially built structure in the apo PWWP
domain, refolds into a visible and rigid α-helix in the DNA complex notably. The swapped
PWWP domain interacts with the minor groove of 10-bp SMYD1 via residues Lys19, Gly22,
Arg79 and Lys80 with variable characters on loops 1 and 4 at the swapped C/N terminus,
and the structure becomes more stable and rigid than the apo form. Together with
physiological assays, these novel structural findings may provide new insights into the
mechanism of DNA binding and the functional process of HDGF.

Key words: HDGF, PWWP domain, SMYD1, domain swapping

INTRODUCTION

Human HDGF belongs to the HDGF-related protein (HRP) family and is highly expressed
in the tumour cell lines, developing heart and the normal tissue ubiquitously with angiogenic
and mitogenic activities (Yang and Everett, 2009). HDGF participates in different cellular
processes, such as cardiovascular differentiation (Everett, 2002), the formation of vascular
lesion (Everett et al., 2000) and astrocyte proliferation (Crossin et al., 1997). The over-
expressed HDGF is related to several kinds of cancers such as hepatocellular carcinoma
(Chen et al., 2015), non-small cell lung cancer (Iwasaki et al., 2005), etc.

Human HDGF comprises the chromatin-associated N-terminal PWWP domain which is
capable of binding the nonspecific DNA, specific SMYD1 promoter and histone (Yang and
Everett, 2007). Some of the proteins in eukaryotes contain the highly conserved PWWP
domains from unicellular organisms to human species and most of them belong to
chromatin-associated proteins (Rondelet et al., 2016). The variable C-terminus of HDGF
which participates in various cellular processes is in charge of translocation and gene
regulation. (Kishima et al., 2002; Wang et al., 2011).

To date, the conserved PWWP domain and complexes with histone-related peptides
structures have been solved (Qiu et al., 2002; Sue et al., 2004; Vezzoli et al., 2010; Wu et
al., 2011). However, the interaction between DNA and HDGF remains unclear because of a
lack of comparatively of essential knowledge about its exact structure in protein-DNA
complex. In the thesis, we report the first crystal structures of the human HDGF PWWP
domain with a 10-bp SMYD1 in complex and its unbound apo form. Our studies provide
new insights into the PWWP-DNA interaction which could facilitate study about the role of
the PWWP domain in nucleosomal context.

MATERIALS AND METHODS

The DNA sequence of HDGF has been mutated on the rare codon from the library of human
fetal brain cDNA (Stratagene, La Jolla, CA) (Hu et al., 2003). The constructs of HDGF and
the PWWP domain have constructed into artificial vectors between NdeI and EcoRI
restriction sites for further production of the recombinant N-terminal His-tagged fusion
protein.

The HDGF and the PWWP domain constructs were transformed and over-expressed in
Escherichia coli (E. coli) BL21 (DE3) and BL21-Codon Plus ® -RIL, respectively.
Overexpression of HDGF and the PWWP domain were induced with 0.5 mM and 1 mM
IPTG (isopropyl β-D-thio-galactopyranoside) for overnight at 37 °C, respectively. The His-
tag fusion proteins were purified from the supernatant after sonication based on Ni 2+ -NTA
agarose column (GE healthcare). The endogenous DNA from E. coli was then removed from
the purified proteins were then removed by the anion-exchange chromatography (Hitrap Q)
owing to the distinct pI values between DNA and proteins. The protein with various lengths
designed SMYD1 complexes were further collected by size-exclusion chromatography
(Superdex-200).

Crystallization trials were performed using several crystal-screening kits with 96-well plates
(JET Biofil) based on the hanging-drop vapor-diffusion method. The apo PWWP domain
crystals appeared under the condition containing sodium chloride (0.2 M) and polyethylene
glycol (PEG) 4000 (25%, w/v) and Tris (0.1 M, pH 8.5). The crystals of PWWP-SMYD1
complex were obtained in a condition containing sodium phosphate dibasic (0.09 M),
sodium nitrate (0.09 M), PEG 1000 (12.5%), PEG 4000 (12.5%, w/v) and Tris; Bicine (0.1
M, pH 8.5).

The initial phase of the apo PWWP domain has been solved by the HDGF2 PWWP domain
(PDB entry: 3QBY) with one PWWP domain in asymmetric unit, and the structure was
refined to 3.3 Å resolution, whereas 10-bp SMYD1 in asymmetric unit was determined at
2.84 Å . All structures were determined by the molecular replacement method with the
program, Molrep (Vagin and Teplyakov, 1997).

RESULTS AND DISCUSSION

We have improved the expression yield of human HDGF by rare codon mutation for
structural studies, confirmed that the binding ability of both NCL and DNA for HDGF is
through its N-terminal PWWP domain and the addition of SMYD1 interferes the binding
capability of NCL for HDGF, and determined the first crystal structures of human HDGF
PWWP domain with 10-bp SMYD1 complex and its apo form, respectively.

The apo PWWP domain reveals a monomeric structure with four β-strands, two α-helices
and a flexible loop2 with diminished electron density. However, the PWWP domain
undertakes domain swapping to alter markedly its secondary structures and transform the
overall conformation through a globular monomer into an extended dimer with newly
formed αC upon DNA binding. The flexible loop2 in the apo PWWP domain is replaced by
newly formed αC upon DNA binding in the PWWP-SMYD1 complex and functions as hinge
loop which participates in domain swapping. (Fig. 1).

The PWWP domain interacts with the minor groove of DNA through the residues with
variable characters, Lys19, Gly22, Arg79 and Lys80, at DNA binding loops: 1 and 4 from
two chains at C/N terminus of the swapped dimer. Together with physiological assays, these
novel structural findings may provide new insights into the mechanism of DNA binding and
the functional process of HDGF.

The part of potential DNA binding residues in the structures monitored from NMR chemical
shift perturbation (PDB entries: 2B8A, 2M16, 2GFU) are consistent with the DNA-binding
area in the HDGF PWWP-SMYD1 complex, suggesting that these PWWP domains may
react to DNA through loops: 1 and 4.

Figure 1. The density at hinge loop region in the apo PWWP domain and PWWP-
SMYD1 complex and schematic representation of the dimeric swapped PWWP.
(A) The incomplete density causes the difficulty of structure trace from Ala36 to Lys44 (blue
mesh, 2F o -F c at 1.5 σ). (B) The well determined and defined αC structure from Asp31 to
Lys44 could be covered within the continuous density (blue mesh, 2F o -F c at 1.5 σ). (C) The
involved swapped region is shown in green and the other regions are in red in one monomer
(left panel). The other molecule of a dimer is shown in gray (right panel). The DNA-binding
loops are shown in blue, whereas the residues of the PWWP motif are indicated in stick.

CONCLUSION

In this study, we have increased the expression yield of HDGF for structural studies
successfully, confirmed that the binding capability of both DNA and NCL for HDGF through
its N-terminal PWWP domain and addition of SMYD1 interferes the binding capability of
NCL for HDGF, and determined the first crystal structures of human HDGF PWWP domain
with 10-bp SMYD1 complex and its apo form at 2.84 Å and 3.3 Å resolution, respectively.
The PWWP domain undertakes domain swapping to alter markedly its overall conformation
through a globular monomer into an extended dimer upon DNA binding. The PWWP-DNA
complex is more stable and rigid compared to the apo form. The PWWP domain interacts
with the minor groove of DNA through the residues with variable characters at DNA binding
loops: 1 and 4 from two chains at C/N terminus of the swapped dimer. Together with
physiological assays, these novel structural findings may provide new insights into the
mechanism of DNA binding and the functional process of HDGF.
論文目次 Table of Contents
Chinese Abstract(中文摘要) ........................................................................................ I
Abstract .............................................................................................................................. II
Acknowledgments ............................................................................................................ VI
Table of Contents ........................................................................................................... VII
Contents of Tables ............................................................................................................. XI
Contents of Figures .......................................................................................................... XII
Abbreviation List .............................................................................................................. XV
Chapter 1 Research Background ..................................................................................... 1
1-1 The relations between HDGF and cancers ........................................................ 1
1-2 Chromatin-related N-terminal PWWP domain.................................................. 1
1-3 DNA binding ability of N-terminal PWWP domain .......................................... 3
1-4 The relations among histone modification, SMYD1 and HDGF ...................... 4
1-5 Mitogenic activity by variable C-terminus of HDGF ........................................ 5
1-6 Current structures and complexes about HDGF PWWP domain ...................... 5
1-7 Research objectives ........................................................................................... 6
Chapter 2 Materials and Methods ................................................................................... 8
2-1 Site-directed mutagenesis of HDGF for rare codon change .............................. 8
2-2 Construction of the HDGF PWWP 1-100 domain ................................................ 8
2-3 Expression and purification of HDGF from E. coli ........................................... 9
2-4 Expression and purification of HDGF PWWP 1-100 domain from E. coli ........ 10
2-5 Stability test of HDGF and the PWWP domain ............................................... 11
2-6 Colony formation assay .................................................................................... 11
2-7 Secondary structure analyses of the apo PWWP domain and HDGF .............. 11
2-8 Purification of the HDGF PWWP-SMYD1 complex ....................................... 12
2-9 Solid-phase binding assay ................................................................................ 12
2-10 Competitive assay ............................................................................................ 13
2-11 Crystallization of HDGF apo PWWP and PWWP-SMYD1 complex ............. 13
2-12 X-ray data collection of HDGF apo PWWP domain and PWWP-SMYD1
complex, structure determination and refinement ........................................... 14
Chapter 3 Results ............................................................................................................ 17
3-1 Low expression yield of HDGF from E. coli .................................................. 17
3-2 Preparation of large amount HDGF and the PWWP domain from E. coli ...... 18
3-3 The stability of HDGF and the PWWP domain .............................................. 19
3-4 Functional assay of HDGF and the PWWP domain by cell assay .................. 20
3-5 Functional assay of HDGF and the PWWP domain by DNA binding assay .. 21
3-6 SMYD1 binding attenuates the interaction of HDGF with NCL ..................... 21
3-7 The flexibility and solubility of HDGF and the PWWP domain .................... 22
3-8 Crystallization of apo HDGF, the PWWP domain, HDGF-SMYD1 and
PWWP-SMYD1 complex ................................................................................ 23
3-9 Overall structure of the apo PWWP domain ................................................... 24
3-10 Multiple forms of the HDGF apo PWWP domain .......................................... 25
3-11 Overall structure of the domain-swapped PWWP-SMYD1 complex .............. 25
3-12 Interactions between the PWWP domain and SMYD1 .................................... 28
3-13 Structural and B-factor comparisons of the PWWP-SMYD1 complex and apo
form ................................................................................................................. 29
Chapter 4 Discussion ....................................................................................................... 31
4-1 The difficulty of HDGF crystallization ........................................................... 31
4-2 SMYD1 binding attenuates the interaction of HDGF with NCL ..................... 31
4-3 The multiform of the PWWP domain for DNA binding ................................. 32
4-4 Dimerization by domain swapping of the HDGF PWWP domain for DNA
binding ............................................................................................................. 35
4-5 Interactions between the PWWP domain and SMYD1 .................................... 38
4-6 Structural comparisons and implications to other PWWP domains ................ 38
4-7 The importance of the positively charged distribution in the complex ........... 41
4-8 Mechanism hypothesis of DNA binding and functional process .................... 41
4-9 The anticipative applications depend on HDGF PWWP-SMYD1 complex
structure in the future ...................................................................................... 43
Chapter 5 Conclusion...................................................................................................... 44
References ........................................................................................................................ 46
Tables ................................................................................................................................ 56
Figures .............................................................................................................................. 65
Related Paper Publications .......................................................................................... 104

Contents of Tables
Table 1. Summary of primers utilized for the study of HDGF ................................... 57
Table 2. Storage buffer conditions for stability test of HDGF and the PWWP
domain ........................................................................................................... 58
Table 3. Crystallographic data and refinement statistics of the HDGF apo PWWP
domain and the PWWP-SMYD1 complex ..................................................... 59
Table 4. The numbers of pair interactions correspond to those in the dimerization of
the PWWP domain (Fig. 20) ......................................................................... 60
Table 5. Detailed interactions of each DNA-binding residue and the DNA
nucleotide ...................................................................................................... 61
Table 6. Normalized B-factor values at the regions of structural differences between
the PWWP-SMYD1 complex and the apo PWWP domain ........................... 62
Table 7. The numbers of pair interactions correspond to those in Fig. 27D ............... 63
Table 8. Hydrogen-bonding residue pairs of the swapped domain in the PWWP-
SMYD1 complex and the apo PWWP domain .............................................. 64

Contents of Figures
Figure 1. The improvement of expression of HDGF ..................................................... 66
Figure 2. Expression results of HDGF under different culture media ........................... 67
Figure 3. The expression results of HDGF after mutation for codon usage strategy ..... 68
Figure 4. NTA purification results of HDGF and the PWWP domain ........................... 69
Figure 5. Removal of the endogenous DNA from E. coli for HDGF and the PWWP
domain by ion-exchange chromatography ...................................................... 70
Figure 6. Observation of multiple forms of HDGF and the PWWP domain with the
Superdex-200 size-exclusion chromatography ............................................... 71
Figure 7. The stability of HDGF under various conditions ............................................ 72
Figure 8. The stability of HDGF PWWP domain under various conditions.................. 73
Figure 9. The biological activity of human HDGF and the PWWP domain ................. 74
Figure 10. The DNA binding ability of HDGF and the PWWP domain .......................... 75
Figure 11. The NCL-binding ability of HDGF and the PWWP domain .......................... 76
Figure 12. The secondary structures of HDGF and the PWWP domain based on SRCD 77
Figure 13. The crystals of apo PWWP domain and PWWP-SMYD1 complex ............... 78
Figure 14. Overall structure of the HDGF apo PWWP domain ...................................... 79
Figure 15. The symmetry-related apo PWWP domains in the crystals of hexagonal space group P6 4 22 .......................................................................................... 81
Figure 16. Analyses of interactions between the PWWP domain with various SMYD1
lengths by size-exclusion chromatography (Superdex-200) ........................... 82
Figure 17. The initial density map of PWWP-SMYD1 complex...................................... 83
Figure 18. Overall structure of the PWWP-SMYD1 complex .......................................... 84
Figure 19. Schematic representation of the dimeric swapped PWWP structure .............. 85
Figure 20. The interactions between each domain in the dimeric PWWP-SMYD1
complex ........................................................................................................... 86
Figure 21. Interactions in the PWWP-SMYD1 complex .................................................. 87
Figure 22. Distances between loops 1 and 4 in the PWWP-SMYD1 complex ................ 89
Figure 23. Stereo view of the charge distribution from surface in the PWWP-SMYD1
complex ........................................................................................................... 90
Figure 24. Comparisons of B-factors at the large structural differences between the
complex and the apo forms ............................................................................. 91
Figure 25. The flexibility of the hinge region between the apo PWWP domain (loop2)
and PWWP-SMYD1 complex (αC) based on the electron density map ......... 92
Figure 26. The possibility of non-swapped apo dimeric PWWP domain ........................ 93
Figure 27. Structural comparisons of domain swapping proteins, RNase A, apo PWWP
domain and PWWP-SMYD1 complex ............................................................ 94
Figure 28. The structural comparison of the methylated peptides binding region
between the PWWP domains of swapped HDGF complex and non-swapped
HDGF2............................................................................................................ 96
Figure 29. Structural comparisons of various PWWP domains ....................................... 97
Figure 30. The distance between the swapped HDGF PWWP domains .......................... 99
Figure 31. Sequence alignments and structural comparisons of various PWWP
domains ......................................................................................................... 100
Figure 32. Proposed mechanism of HDGF in gene regulation ...................................... 102
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