以結構為基礎探討人類嗜酸性球核醣核酸水解酶與肝素之結合模式

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研究生：	洪達任 Hung, Ta-Jen
論文名稱：	以結構為基礎探討人類嗜酸性球核醣核酸水解酶與肝素之結合模式 Structural basis for differential heparin binding modes of human eosinophil ribonucleases
指導教授：	張大慈 Chang, Dah-Tsyr
口試委員:	洪上程 Hung, Shang-Cheng 孫玉珠 Sun, Yuh-Ju 蘇士哲 Sue, Shih-Che 黃群偉 Huang, Chiun-Wei 張顥騰 Chang, Hao-Teng
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 分子與細胞生物研究所 Institute of Molecular and Cellular Biology
論文出版年：	2013
畢業學年度：	102
語文別：	英文
論文頁數：	184
中文關鍵詞：	人類嗜酸性白血球核醣核酸酶、嗜酸性白血球陽離子蛋白、嗜酸性白血球神經毒蛋白、肝素、糖胺聚糖、石英振盪微天平、磁減量試驗
外文關鍵詞：	eosinophil ribonuclease, eosinophil cationic protein, eosinophil derived neurotoxin, heparin, glycosaminoglycans, quartz crystal microbalance, magnetic reduction assay
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人類嗜酸性白血球陽離子蛋白(eosinophil cationic protein，ECP)及嗜酸性白血球神經毒蛋白(eosinophil derived neurotoxin，EDN)皆由活化的嗜酸性白血球分泌至血液中，並隸屬於人類核醣核酸水解酶A家族(RNase A superfamily)。ECP與EDN具有極高的序列及結構相似性，然而兩者之生物功能卻不盡相同。本研究以分子對接(molecular docking)模擬ECP/EDN與肝素聚己糖之交互作用，發現ECP序列中之Gln40及His64形成鉗狀結構以穩定與其結合的肝素聚己糖，而EDN則無相似的結構。此外Arg105亦被預測對ECP與肝素聚己糖交互作用具有相當貢獻。為了釐清預測的真實性，Gln40、His64以及Arg105等胺基酸透過點突變置換成丙氨酸(Ala)，並運用恆溫滴定熱量計(isothermal titration calorimetry，ITC)測量ECP突變株與肝素間結合力的變化。此外，本研究利用石英振盪微天平(quartz crystal microbalance，QCM)以及磁減量試驗(magnetic reduction assay，MRA)兩種新穎分子親和力偵測技術測量由ECP序列衍生之細胞穿透胜肽(NYRWRCKNQN，CPPecp)以及肝素結合胜肽(YRWRCK，HBPecp)的肝素/糖胺聚糖結合能力。本研究分析ECP與EDN與肝素結合模式的差異，進而探討ECP與EDN之序列、結構、以及功能的相關性。本論文之主要貢獻為發現ECP/EDN與肝素/糖胺聚糖結合模式與結合強度的差異性，及ECP/EDN與細胞間作用相異性的原因，進而瞭解相關免疫疾病的分子機制。

Human eosinophil cationic protein (ECP) and eosinophil derived neurotoxin (EDN) are two ribonuclease A family members secreted by activated eosinophils. They share conserved catalytic triad and similar three dimensional structures. ECP and EDN are heparin binding proteins with diverse biological functions. Here, a novel molecular model for ECP/EDN binding of heparin hexasaccharide, [GlcNS(6S)-IdoA(2S)]3, was predicted. Interestingly, Gln40 and His64 on ECP formed a clamp-like structure to stabilize heparin hexasaccharide in our model, which was not observed in the corresponding residues on EDN. To validate our prediction, mutant ECPs including ECP Q40A, H64A, R105A, and double mutant ECP Q40A/H64A were generated, and their binding affinity for heparins were measured by isothermal titration calorimetry (ITC). Weaker binding of ECP Q40A/H64A of all heparin variants suggested that Gln40-His64 clamp contributed to ECP-heparin interaction significantly. Besides, binding affinities of a multi-functional peptide (NYRWRCKNQN, CPPecp), containing major heparin binding region of ECP, to heparin derivatives and glycosaminoglycans (GAGs) were determined by quartz crystal microbalance (QCM) and magnetic reduction assay (MRA). Moreover, a peptide containing minimum length to interact with heparin (YRWRCK, HBPecp) was also used. In conclusion, our in silico and in vitro data demonstrate that ECP uses not only major heparin binding region but also other surrounding residues to interact with heparin. Discovery of such correlation in sequence, structure, and function is a unique feature of only higher primate ECP, but not EDN, as well as differential binding mode, binding affinity, and cellular interaction between ECP and EDN facilitate further understanding of molecular mechanisms of immune diseases.

中文摘要    1
Abstract    2
Acknowledgement    3
Table of Contents    4
Abbreviation    12
Chapter 1  Introduction    17
1-1  Eosinophil    17
1-2  Human RNaseA superfamily    17
1-3  Eosinophil RNases    18
1-4  Structure features of eosinophil RNases    18
1-5  Eosinophil cationic protein    19
1-6  Eosinophil derived neurotoxin    20
1-7  Heparin and glycosaminoglycans    21
1-8  Interaction between heparin and eosinophil RNases    21
1-9  Heparin binding motif    22
1-10  Heparin binding regions of eosinophil RNases    22
1-11  Amino acids involved in ECP-heparin interaction    23
1-12  Multi-functional peptide derived from eosinophil RNases    24
1-13  Biosensors for molecular interaction detection    24
1-14  Isothermal titration calorimetry (ITC)    25
1-15  Quartz crystal microbalance (QCM)    25
1-16  Magnetic reduction assay (MRA)    26
1-17  Surface plasmon resonance (SPR)    27
1-18  Lanthanide labeling for fluorescence measurement    27
1-19  Native chemical ligation (NCL)    28
1-20  Aims    29
Chapter 2  Materials and Methods    30
2-1  GAGs and heparin derivatives    30
2-2  Antibodies and chemicals    30
2-3  Fluorescence-assisted carbohydrate electrophoresis (FACE)    31
2-4  In silico docking simulation of heparin hexasaccharide and dodecasaccharide to ECP and EDN    31
2-5  Construction, expression and purification of wild type and mutant ECPs    32
2-6  Enzymatic activity assay of wild type and mutant ECPs    33
2-7  ITC experiments    33
2-8  Immuno-fluorescence staining and confocal microscopy    34
2-9  Peptide syntheses    34
2-10  Eu-fluorescence analysis    35
2-11  TNBS method    35
2-12  Determination of Eu Content    36
2-13  DTPAah modification of QCM microchip and Eu chelation    36
2-14  Amino group quantification by DTPA-aminoacetaldehyde modification using Eu complexation    36
2-15  Maleimide modification of the QCM N-link sensor chip    37
2-16  Eu labeled BSA (Eu-BSA, TJ-1)    37
2-17  CPPecp peptide immobilized QCM N-link sensor chip    37
2-18  QCM experiments    38
2-19  Preparation of aminoxy functionalized silica gel (TJ-2)    38
2-20  Deprotection of Boc on TJ-2 (TJ-3)    38
2-21  Preparation of 6-O-dansylated 1,2-3,4-di-O-isopropylidene galactopyranose (TJ-4)    39
2-22  De-protection of 6-O-dansylated 1,2-3,4-di-O-isopropylidene galactopyranose (6-O-Dan-Gal; TJ-5)    39
2-23  NMR experiments    39
2-24  Dextran-coated 60 nm nanoparticle synthesis (NP-OH, TJ-NP1)    40
2-25  Amino-terminated nanoparticle synthesis (NP-NH2, TJ-NP2)    40
2-26  Carboxylic acid-terminated nanoparticle synthesis (NP-COOH, TJ-NP3)    40
2-27  Glycine thioester synthesis (TJ-7 and TJ-10)    40
2-28  Deprotection of Boc (TJ-8 and TJ-11)    44
2-29  EDC/NHS cross-linking of Boc-glycine or NP-COOH with glycine thioester    46
2-30  Nanoparticle iron content analysis    48
2-31  Inductively coupled plasma-atomic emission spectrometer (ICP-AES) experiments    49
2-32  Removal of the alloc protecting group on HBPecp peptidyl resin    49
2-33  Fmoc labeling of HBPecp peptidyl resin    49
2-34  TFA cleavage of HBPecp peptidyl resin    49
2-35  High-performance liquid chromatography (HPLC) purification    50
2-36  MRA experiments    50
2-37  Statistical analysis    52
Chapter 3  Structural basis of eosinophil RNases in heparin binding    53
3-1  Sequence alignment of eosinophil RNases    53
3-2  Expression and purification of wild-type ECP    53
3-3  Influence of heparin chain length in ECP binding    54
3-4  Accuracy of in silico docking simulation    55
3-5  Binding model of ECP to heparin hexasaccharide    56
3-6  Binding model of EDN to heparin hexasaccharide    57
3-7  Comparison of ECP/EDN in complex with heparin hexasaccharide    58
3-8  Expression and purification of mutant ECPs    58
3-9  Determination of binding affinities between wtECP/mutant ECPs and heparin derivatives by ITC    59
3-10  Secondary heparin-binding site on ECP    61
3-11  Binding of ECP to heparin dodecasaccharide    62
3-12  Endocytosis of ECP and inhibitor screening from Chinese herbs    62
Chapter 4  Determination of binding affinities between heparin derivatives/GAGs and heparin binding peptide derived from ECP using QCM    64
4-1  Superimposition of ECP/EDN-heparin hexasaccharide complex by fitting residues 32–41    64
4-2  Determination of functional amino groups on PEI by TNBS method    65
4-3  Determination of functional amino group on QCM N-link sensor chip by pyridoxal phosphate    66
4-4  Determination of functional amino group on QCM N-link sensor chip by DTPA and Eu method    66
4-5  Immobilization of maleimide functional groups on QCM N-link sensor chip    68
4-6  Determination of protein binding density on QCM N-link sensor chip using Eu-BSA    68
4-7  Immobilization of CPPecp on QCM N-link sensor chip    69
4-8  Determination of binding affinity between CPPecp and heparin by QCM    69
4-9  Determination of binding affinities between CPPecp and heparin derivatives by QCM    70
4-10  Determination of binding affinities between CPPecp and GAGs by QCM    70
4-11  Aminoxy functionalized silica gel (TJ-3)    71
4-12  Dansylation of galactose (6-O-Dan-Gal; TJ-5)    72
4-13  Conjugation of 6-O-Dan-Gal on aminoxy functionalized silica gel (TJ-6)    72
Chapter 5  Determination of binding affinities between heparin derivatives/GAGs and heparin binding peptide derived from ECP using MRA    74
5-1  Nanoparticle synthesis    74
5-2  Glycine ethyl thioglycolate thioester linker    74
5-3  Glycine ethyl thioglycolate thioester-terminated nanoparticle synthesis    75
5-4  Glycine methyl-3-mercaptopropionate thioester linker    76
5-5  Glycine methyl-3-mercaptopropionate thioester-terminated nanoparticle synthesis    76
5-6  Fmoc-labeled HBPecp synthesis    77
5-7  Determination of binding affinities between CPPecp and GAGs by MRA    78
Chapter 6  Discussion    79
Figures    86
Figure 1-1  Multifunctional effects of eosinophils    86
Figure 1-2  Amino acid sequence alignment of eight human RNases    87
Figure 1-3  Three-dimensional structures of human RNaseA superfamily members    88
Figure 1-4  Crucial regions and key residues on ECP involved in biological properties    89
Figure 1-5  Location and structure of HSPG    90
Figure 1-6  Structures of GAGs    91
Figure 1-7  Principle of ITC    92
Figure 1-8  Principle of QCM action    93
Figure 1-9  Principle of MRA    94
Figure 1-10  Principle of SPR    95
Figure 1-11  DTPAah modification of amino group    96
Figure 3-1  Sequence alignment of human eosinophil RNases and HBRs    97
Figure 3-2  Expression and purification of ECP-6His    98
Figure 3-3  Requirement of heparin length for interaction with wtECP    99
Figure 3-4  Estimation of in silico docking accuracy and performance    100
Figure 3-5  Predicted ECP-heparin hexasaccharide interaction    102
Figure 3-6  Predicted EDN-heparin hexasaccharide interaction    104
Figure 3-7  Putative heparin binding clamp in ECP with corresponding residues in EDN    106
Figure 3-8  Purification of wtECP and mutant ECPs    107
Figure 3-9  Binding isotherm for interaction of wild type/mutant ECP with heparin hexasaccharide    109
Figure 3-10  Predicted secondary heparin binding sites on wtECP surface    112
Figure 3-11  Predicted wtECP-heparin dodecasaccharide interaction    114
Figure 3-12  Inhibition of MBP-ECP translocation by Chinese herbs    116
Figure 4-1  Comparison of the binding residues (32-41) of human ECP and EDN    117
Figure 4-2  Amount of pyridoxal phosphate binding on QCM N-link sensor chip    118
Figure 4-3  Amounts of Eu ions bound on modified QCM N-link sensor chips    119
Figure 4-4  Amounts of Eu-BSA binding to QCM N-link sensor chips    120
Figure 4-5  Binding affinities of CPPecp to heparin molecules with different lengths using QCM    121
Figure 4-6  Binding affinities of CPPecp to heparin derivatives using QCM    122
Figure 4-7  Binding affinities of CPPecp to GAGs using QCM    123
Figure 4-8  Binding isotherm for CPPecp interaction with GAGs    125
Figure 4-9  Conjugation of 6-O-Dan-Gal on aminoxy functionalized silica gel    126
Figure 5-1  Glycine ethyl thioglycolate thioester synthesis    127
Figure 5-2  Boc-glycine-glycine thioester (TJ-9) synthesis    128
Figure 5-3  Thioester group determination using IR spectroscopy    128
Figure 5-4  Sulfur determination using X-ray photoelectron spectroscopy (XPS)    129
Figure 5-5  Glycine methyl-3-mercaptopropionate thioester synthesis    130
Figure 5-6  Analysis of Fmoc-labeled HBPecp    131
Figure 5-7  Purification of Fmoc-HBPecp    132
Figure 5-8  Binding affinities of HBPecp/CPPecp to LMWH determined by MRA    133
Figure 5-9  Binding affinities of CPPecp to HMWH/CSC determined by MRA    134
Figure 6-1  Sequence alignment of primate human eosinophil RNases and HBRs    135
Figure 6-2  Docking model of ECP against a heparin dodecasaccharide    136
Tables    137
Table 1-1  Comparison of catalytic and biological properties between eosinophil RNases    137
Table 1-2  Reported regions and residues in ECP involved in biological functions    138
Table 2-1  Gradient conditions of HPLC for Fmoc-HBPecp    139
Table 3-1  RNase activity of wtECP and mutant ECPs    140
Table 3-2  Interaction between wild type ECP and heparin hexasaccharide    141
Table 3-3  Calculated binding energy of heparin hexasaccharide to various ECP mutants and contribution of individual amino acid    143
Table 3-4  Interaction between wild type EDN and heparin hexasaccharide    144
Table 3-5  Calculated binding energy of heparin hexasaccharide to various EDN mutants and contribution of individual amino acid    145
Table 3-6  Thermodynamic parameters for interaction between wild type/mutant ECP and heparin derivatives    146
Table 4-1  Amount of functional amino groups on modified QCM N-link sensor chips    147
Table 4-2  Binding affinity of each GAG to CPPecp determined by QCM    147
Table 5-1  Sulfur concentration in different NPs.    148
Table 5-2  Sulfur concentration in each experiment.    148
Table 6-1  List of heparin-protein complexes    149
Table 6-2  Comparison of binding affinities among different methods    150
Table 6-3  Pros and Cons of ITC, QCM and MRA    151
Schemes    152
Scheme 1-1  Mechanism of NCL    152
Scheme 4-1  DTPA and Eu method using DTPAah    153
Scheme 4-2  DTPA and Eu method using DTPA aminoacetaldehyde    153
Scheme 4-3  EMCS immobilization on QCM N-link sensor chip    154
Scheme 4-4  Preparation of Eu-BSA (TJ-1)    154
Scheme 4-5  Immobilization of CPPecp on QCM N-link sensor chip    155
Scheme 4-6  Aminoxy acetic acid conjugated amino functionalized silica gel (TJ-2 & TJ-3)    155
Scheme 4-7  Preparation of 6-O-Dansyl-Galactose (TJ-4 & TJ-5)    155
Scheme 4-8  Conjugation of 6-O-Dan-Gal on aminoxy functionalized silica gel (TJ-6)    155
Scheme 5-1  Iron oxide nanoparticle syntheses (60 nm)    156
Scheme 5-2  Glycine ethyl thioglycolate thioester linker synthesis (TJ-7 and TJ-8)    156
Scheme 5-3  EDC/NHS cross-linking of Boc-glycine and thioester linker (TJ-9)    156
Scheme 5-4  Thioester-terminated nanoparticle synthesis    156
Scheme 5-5  Glycine methyl-3-mercaptopropionate thioester linker synthesis (TJ-10 and TJ-11)    157
Scheme 5-6  Thioester terminated-nanoparticle synthesis with a glycine methyl-3- mercaptopropionate thioester linker    157
Scheme 5-7  Fmoc-labeled heparin-binding peptide synthesis    157
Scheme 5-8  Heparin binding NP synthesis using EDC/NHS cross-linking method    157
Scheme 6-1  Click reaction    158
References    159
Appendix I  List of eosinophil RNases heparin binding regions and peptide    168
Appendix II  List of products    169
Appendix III  Structure of heparin-protein complexes    173

                                

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