蛋白質家族中獨特胜肽序列之鑑定與分析｜國立清華大學博碩士論文庫

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研究生：	張顥騰 Hao-Teng Chang
論文名稱：	蛋白質家族中獨特胜肽序列之鑑定與分析 Identification od characterization of unique peptide motifs in members of protein families
指導教授：	張大慈博士 Margaret Dah-Tsyr Chang, PhD
口試委員:
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生命科學系 Department of Life Sciences
論文出版年：	2006
畢業學年度：	94
語文別：	英文
論文頁數：	95
中文關鍵詞：	抗原設計、抗原決定位置、彎曲結構、胜肽抗原、蛋白質家族、強化合併演算法、獨特胜肽序列
外文關鍵詞：	antigen design, epitope, loop, peptide antigen, protein family, reinforced merging algorithm, unique peptide motif
相關次數：	點閱：3 下載：0
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蛋白質家族通常具有高度相似的胺基酸序列、生物功能及三級結構。然而，有些序列相似度高的酵素卻具有不同的功能，可能的原因之一是其序列多變區內具有獨特胜肽序列(unique peptide motif, UPM)，能與其他蛋白質或細胞分子交互作用，因而產生特殊的生物活性。運用生物資訊及分子生物學方法在蛋白質家族成員中找出序列特徵，對於鑑定及分析獨特胜肽序列非常重要。本研究發展一套強化合併演算法(reinforce merging algorithm, RMA)，用以分析多種蛋白質家族的胺基酸序列，包括核醣核酸水解酶A (ribonuclease A, RNaseA)、表皮生長因子受體(epidermal growth factor receptor, EGFR)、基質金屬蛋白酶(matrix metalloproteinase, MMP)、Sma-and-Mad關聯蛋白(Sma-and-Mad related protein, Smad)、酪氨酸激酶下游蛋白(downstream of tyrosine kinase, DOK)和羧基胜肽水解酶(carboxypeptidase, CP)等，從中鑑定出多串連續獨特胜肽序列。在跨品種同源蛋白質序列比較方面，則以哺乳動物核醣核酸水解酶A與細菌MsbA同源蛋白組為例，亦鑑定出多串獨特胜肽序列。將所獲資訊與蛋白質結構資料比對，發現由強化合併演算法所鑑定之獨特胜肽序列大部分出現在蛋白質三級結構的表面，特別是彎曲結構區域(loop)。本研究亦證明部分獨特胜肽序列與連續性抗體結合位置(sequential epiotpes)相關，例如□RNase2、mAb 3C1、□MMP1、□MMP3和□CPE等五種單株抗體及D112-P123 Ab、□ErbB2 N-term和□DOK2等三種多株抗體之抗原決定位置相符。此外，大部分獨特胜肽序列與PROTEAN預測到的抗原性(antigenecity)序列具有高度相關性，較大規模的抗體資料庫分析顯示本研究方法預測的獨特胜肽序列作為抗原決定位置的準確度達到百分之七十以上。此外，本研究亦探索獨特胜肽序列與非抗體蛋白質、細胞、受質與配體等其他分子的交互作用之相關性，並能舉出實例印證之。
總結而言，本論文結合生物資訊及分子生物學實驗方法，首度報導能迅速鑑定蛋白質家族成員中具有獨特序列特異性的胜肽片段之新穎方法，並以多重序列比對探索此獨特胜肽序列與蛋白質結構、功能及抗原決定位置的相關性，並能據此設計實驗證明其準確性及實用性。

Members of protein families often have highly conserved sequences; most of these sequences carry identical biological functions and possess similar three-dimensional structures. However, enzymes with high sequence identity may acquire differential functions other than the common catalytic ability. It is conceivable that each of their variable regions consists of a unique peptide motif (UPM), which selectively interacts with other cellular proteins, rendering additional biological activities. The ability to identify and localize such UPMs is paramount in recognizing the characteristic role of each member of a protein family. In this study, we have developed a reinforced merging algorithm (RMA) with which non-gapped UPMs were identified in a variety of query protein sequences including members of human ribonuclease A (RNaseA), epidermal growth factor receptor (EGFR), matrix metalloproteinase (MMP), Sma-and-Mad related protein (Smad), downstream of tyrosine kinase (DOK) and carboxypeptidase (CP) protein families. Cross species comparison of two homologous protein sets, RNaseAs and MsbAs, were also investigated. The UPMs identified by RMA generally occupy specific positions in the resolved three-dimensional structures, especially the loop regions on the structural surfaces. These motifs coincide with the recognition sites for antibodies, as the epitopes of five monoclonal antibodies, □RNase2, mAb 3C1, □MMP1, □MMP3 and □CPE, and three polyclonal antibodies, D112-P123 Ab, □ErbB2 N-term and □DOK2 were shown to overlap with the UPMs so mapped. Most of the UPMs were found to correlate well with the potential antigenic regions predicted by PROTEAN. Furthermore, via large scale analysis of an antibody database, an accuracy of 70% can be achieved in terms of mapping a UPM to an epitope. In addition, UPMs are found to correlate well with the regions for protein-protein, protein-cell, enzyme-substrate, and receptor-ligand interactions.
Taken together, we have developed a novel, rapid and efficient methodology for identification of peptide fragments possessing uniqueness from members of protein families employing bioinformatics and molecular biological approaches. The correlation of UPMs with three-dimensional protein structures and functions is excellent such that potential epitopes and interacting motifs that distinguish different members of a protein family can be located.

Table of Contents
Abstract (English) ---------------------------------------------------------------------------    i
Abstract (Chinese) ---------------------------------------------------------------------------    iii
Acknowledgements --------------------------------------------------------------------------    v
Keywords--------------------------------------------------------------------------------------    vi
Abbreviations---------------------------------------------------------------------------------    vii
Availability------------------------------------------------------------------------------------    ix
Table of Contents ----------------------------------------------------------------------------    x
List of Figures --------------------------------------------------------------------------------    xii
List of Tables ---------------------------------------------------------------------------------    xiii

Chapter 1 Introduction---------------------------------------------------------------------    1
1.1    Background-----------------------------------------------------------------------------    2
1.2    RNaseA superfamily ------------------------------------------------------------------    3
1.3    EGFR, MMP, Smad, DOK, and CP families --------------------------------------    6
1.4    Epitopes ---------------------------------------------------------------------------------    7
1.5    Specific aims ---------------------------------------------------------------------------    8
Chapter 2 Materials and Methods-------------------------------------------------------    9
2.1    Development of a Reinforced Merging Algorithm-------------------------------    10
2.1.1 Grouping module -----------------------------------------------------------------    10
2.1.2 Searching module------------------------------------------------------------------    11
2.1.3 Merging module and ranking----------------------------------------------------    14
2.2    Analyses of protein sequences by RMA--------------------------------------------    17
2.3    Localization of the identified UPMs ------------------------------------------------    18
2.4    Plasmid construction and protein expression --------------------------------------    19
2.5    Purification of mature RNase3-------------------------------------------------------    20
2.6    Production and purification of mAb specific to RNase3-------------------------    21
2.7    Western Blotting-----------------------------------------------------------------------    22
2.8    Analysis of protein sequences by PROTEAN-------------------------------------    23
2.9    Large-scale RMA analysis -----------------------------------------------------------    23
Chapter 3 Results---------------------------------------------------------------------------    24
3.1 Identification and correlation of UPMs with structural information -----------    25
3.1.1 Human RNaseA superfamily----------------------------------------------------    25
3.1.2 Protein families with larger molecular weights--------------------------------    26
3.1.2.1 Epidermal growth factor receptor family ---------------------------------    26
3.1.2.2 Matrix metalloproteinase superfamily-------------------------------------    27
3.1.2.3 Sma-and-Mad related protein superfamily--------------------------------    28
3.1.2.4 Downstream of tyrosine kinase and carboxypeptidase families--------    29
3.1.3 Homologous proteins from different species----------------------------------    30
3.1.3.1 Mammal RNaseAs------------------------------------------------------------    30
3.1.3.2 Bacterial MsbAs---------------------------------------------------------------    31
3.2 Biological significance of UPMs----------------------------------------------------    32
3.2.1 Specificity of mAbs against human RNase2 and RNase3-------------------    32
3.2.2 Epitope screening for mAb 3C1-------------------------------------------------    33
3.2.3 Epitope screening for □RNase2-------------------------------------------------    34
3.2.4 Comparison of RMA and PROTEAN------------------------------------------    35
3.2.5 Performance analysis of RMA--------------------------------------------------    36
Chapter 4 Discussion and Conclusion -------------------------------------------------    37
4.1 Specific molecular interaction of UPMs--------------------------------------------    38
4.2 Locolization of UPMs at loop regions----------------------------------------------    39
4.3 Subfamily classification and RMA analysis of MMP and PDE subfamilies---    39
4.4 Identification of UPMs among homologues from different species-------------    41
4.5 Application of UPMs to antigenic peptide design---------------------------------    42
4.6 Comparison of RMA and other pattern recognition algorithms-----------------    45
4.7 Conclusion------------------------------------------------------------------------------    49
References-------------------------------------------------------------------------------------    51
Figures-----------------------------------------------------------------------------------------    61
Tables------------------------------------------------------------------------------------------    83

List of Figures
Figure 1    System configuration and relative parameter settings----------------------    62
Figure 2    The identification of UPMs among eight members of the human
    RNaseA superfamily by RMA------------------------------------------------    63
Figure 3    The identification and localization of UPMs among four members
    of human EGFR family by RMA---------------------------------------------    66
Figure 4    The analysis of MMP1, MMP3, MMP8, MMP10, MMP12 and
    MMP13 subfamily by RMA---------------------------------------------------    68
Figure 5    The analysis of Smad superfamily by RMA---------------------------------    70
Figure 6    The analysis of DOK family by RMA----------------------------------------    72
Figure 7    The analysis of CP family by RMA------------------------------------------    73
Figure 8    The purification of RNase3 and mAb 3C1----------------------------------    75
Figure 9    Specificities of □RNase2 and mAb 3C1-------------------------------------    76
Figure 10     Epitope screening for mAb 3C1 and □RNase2-----------------------------    77
Figure 11    Analyses of RNase2 and RNase3 by RMA and PROTEAN--------------    79
Figure 12     Performance analysis of RMA------------------------------------------------    80
Figure 13    The RMA analysis of PDE families------------------------------------------    81

List of Tables
Table 1     The weighting coefficients for 20 amino acids------------------------------    84
Table 2     The sequences of human protein families for RMA analysis-------------    85
Table 3     The sequences of protein families from different species for RMA
    anaysis----------------------------------------------------------------------------    86
Table 4     Characterization of UPMs in protein families identified by RMA-------    87
Table 5    Characterization of UPMs in homologues from different species iden-
    tified by RMA-------------------------------------------------------------------    90
Table 6    Comparison of UPMs identified by RMA and antigenic regions pre-
    dicted by PROTEAN in RNase3----------------------------------------------    91
Table 7    The large-scare analysis of RMA---------------------------------------------    92

                                

1. Martinez HM: A flexible multiple sequence alignment program. Nucleic Acids Res 1988, 16:1683-1691.
2. Sobel E, Martinez HM: A multiple sequence alignment program. Nucleic Acids Res 1986, 14:363-374.
3. Chappey C, Danckaert A, Dessen P, Hazout S: MASH: an interactive program for multiple alignment and consensus sequence construction for biological sequences. Comput Appl Biosci 1991, 7:195-202.
4. Tang CY, Lu CL, Chang MDT, Tsai YT, Sun YJ, Chao KM, Chang JM, Chiou YH, Wu CM, Chang HT, et al: Constrained multiple sequence alignment tool development and its application to RNase family alignment. J Bioinform Comput Biol 2003, 1:267-287.
5. Lenhof HP, Morgenstern B, Reinert K: An exact solution for the segment-to-segment multiple sequence alignment problem. Bioinformatics 1999, 15:203-210.
6. Nozaki Y, Bellgard M: Statistical evaluation and comparison of a pairwise alignment algorithm that a priori assigns the number of gaps rather than employing gap penalties. Bioinformatics 2005, 21:1421-1428.
7. Miczak A, Ford J, Marian M, Apirion D: RNA processing: new mutants that affect endonucleolytic processing of RNA. Biochem Biophys Res Commun 1983, 114:690-698.
8. Roy MK, Singh B, Ray BK, Apirion D: Maturation of 5-S rRNA: ribonuclease E cleavages and their dependence on precursor sequences. Eur J Biochem 1983, 131:119-127.
9. Beintema JJ, Kleineidam RG: The ribonuclease A superfamily: general discussion. Cell Mol Life Sci 1998, 54:825-832.
10. Wu Y, Mikulski SM, Ardelt W, Rybak SM, Youle RJ: A cytotoxic ribonuclease. Study of the mechanism of onconase cytotoxicity. J Biol Chem 1993, 268:10686-10693.
11. Huang HC, Wang SC, Leu YJ, Lu SC, Liao YD: The Rana catesbeiana rcr gene encoding a cytotoxic ribonuclease. Tissue distribution, cloning, purification, cytotoxicity, and active residues for RNase activity. J Biol Chem 1998, 273:6395-6401.
12. Zhang J, Dyer KD, Rosenberg HF: RNase 8, a novel RNase A superfamily ribonuclease expressed uniquely in placenta. Nucleic Acids Res 2002, 30:1169-1175.
13. Zhang J, Dyer KD, Rosenberg HF: Human RNase 7: a new cationic ribonuclease of the RNase A superfamily. Nucleic Acids Res 2003, 31:602-607.
14. Liao YD, Huang HC, Leu YJ, Wei CW, Tang PC, Wang SC: Purification and cloning of cytotoxic ribonucleases from Rana catesbeiana (bullfrog). Nucleic Acids Res 2000, 28:4097-4104.
15. D'Alessio G: New and cryptic biological messages from RNases. Trends Cell Biol 1993, 3:106-109.
16. Weickmann JL, Elson M, Glitz DG: Purification and characterization of human pancreatic ribonuclease. Biochemistry 1981, 20:1272-1278.
17. Slifman NR, Loegering DA, McKean DJ, Gleich GJ: Ribonuclase activity associated with human eosinophil-derived neurotoxin and eosinophil cationic protein. J. Immunol. 1986, 137:2913-2917.
18. Olssom I, Venge P: Cationic proteins of human granulocytes. I. Isolation of the cationic proteins from the granules of leukaemic myeloid cells. Scand. J. Haematol. 1972, 9:204-214.
19. Rosenberg HF, Dyer KD: Human ribonuclease 4 (RNase 4): coding sequence, chromosomal localization and identification of two distinct transcripts in human somatic tissues. Nucleic Acids Res 1995, 23:4290-4295.
20. Strydom DJ, Fett JW, Lobb RR, Alderman EM, Bethune JL, Riordan JF, Vallee BL: Amino acid sequence of human tumor derived angiogenin. Biochemistry 1985, 24:5486-5494.
21. Rosenberg HF, Dyer KD: Molecular cloning and characterization of a noval human ribonuclease (RNase k6): increasing diversity in the enlarging ribonuclease gene family. Nucleic Acids Res. 1996, 24:3507-3513.
22. Wlodawer A, Bott R, Sjolin L: The refined crystal structure of ribonuclease A at 2.0 A resolution. J Biol Chem 1982, 257:1325-1332.
23. Pous J, Mallorqui-Fernandez G, Peracaula R, Terzyan SS, Futami J, Tada H, Yamada H, Seno M, de Llorens R, Gomis-Ruth FX, et al: Three-dimensional structure of human RNase 1 delta N7 at 1.9 A resolution. Acta Crystallogr D Biol Crystallogr 2001, 57:498-505.
24. Swaminathan GJ, Holloway DE, Veluraja K, Acharya KR: Atomic resolution (0.98 A) structure of eosinophil-derived neurotoxin. Biochemistry 2002, 41:3341-3352.
25. Boix E, Leonidas DD, Nikolovski Z, Nogues MV, Cuchillo CM, Acharya KR: Crystal Structure of Eosinophil Cationic Protein at 2.4 A Resolution. Biochemistry 1999, 38:16794-16801.
26. Terzyan SS, Peracaula R, de Llorens R, Tsushima Y, Yamada H, Seno M, Gomis-Ruth FX, Coll M: The three-dimensional structure of human RNase 4, unliganded and complexed with d(Up), reveals the basis for its uridine selectivity. J Mol Biol 1999, 285:205-214.
27. Acharya KR, Shapiro R, Allen SC, Riordan JF, Vallee BL: Crystal structure of human angiogenin reveals the structural basis for its functional divergence from ribonuclease. Proc Natl Acad Sci U S A 1994, 91:2915-2919.
28. Lehrer RI, Szklarek D, Barton A, Ganz T, Hamann KJ, Gleich GJ: Antibacterial properties of eosinophil major basic protein and eosinophil cationic protein. J Immunol 1989, 142:4428-4434.
29. Rosenberg HF: Recombinant Human Eosinophil Cationic Protein: Ribonuclease Activity is not Essential for Cytotoxicity. J. Biol. Chem. 1995, 270:7876-7881.
30. Bielawski JP, Yang Z: A maximum likelihood method for detecting functional divergence at individual codon sites, with application to gene family evolution. J Mol Evol 2004, 59:121-132.
31. Olayioye MA, Neve RM, Lane HA, Hynes NE: The ErbB signaling network: receptor heterodimerization in development and cancer. Embo J 2000, 19:3159-3167.
32. Nagase H, Woessner JF, Jr.: Matrix metalloproteinases. J Biol Chem 1999, 274:21491-21494.
33. Attisano L, Wrana JL: Signal transduction by the TGF-beta superfamily. Science 2002, 296:1646-1647.
34. Ten Dijke P, Goumans MJ, Itoh F, Itoh S: Regulation of cell proliferation by Smad proteins. J Cell Physiol 2002, 191:1-16.
35. Carpino N, Wisniewski D, Strife A, Marshak D, Kobayashi R, Stillman B, Clarkson B: p62(dok): a constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells. Cell 1997, 88:197-204.
36. Yamanashi Y, Baltimore D: Identification of the Abl- and rasGAP-associated 62 kDa protein as a docking protein, Dok. Cell 1997, 88:205-211.
37. Grimm J, Sachs M, Britsch S, Di Cesare S, Schwarz-Romond T, Alitalo K, Birchmeier W: Novel p62dok family members, dok-4 and dok-5, are substrates of the c-Ret receptor tyrosine kinase and mediate neuronal differentiation. J Cell Biol 2001, 154:345-354.
38. Huang H, Reed CP, Zhang JS, Shridhar V, Wang L, Smith DI: Carboxypeptidase A3 (CPA3): a novel gene highly induced by histone deacetylase inhibitors during differentiation of prostate epithelial cancer cells. Cancer Res 1999, 59:2981-2988.
39. Reznik SE, Fricker LD: Carboxypeptidases from A to z: implications in embryonic development and Wnt binding. Cell Mol Life Sci 2001, 58:1790-1804.
40. Kennett RH: Hybridomas: a new dimension in biological analyses. In Vitro 1981, 17:1036-1050.
41. Welling GW, Weijer WJ, van der Zee R, Welling-Wester S: Prediction of sequential antigenic regions in proteins. FEBS Lett 1985, 188:215-218.
42. Lerner RA: Tapping the immunological repertoire to produce antibodies of predetermined specificity. Nature 1982, 299:593-596.
43. Fanning DW, Smith JA, Rose GD: Molecular cartography of globular proteins with application to antigenic sites. Biopolymers 1986, 25:863-883.
44. Henikoff S, Henikoff JG: Amino acid substitution matrices from protein blocks. Proc Natl Acad Sci U S A 1992, 89:10915-10919.
45. Dayhoff MO, Schwartz RM, Orcutt BC: A model of evolutionary change in proteins. matrices for detecting distant relationships. In: In atlas of protein sequence and structure Edited by MO Dayhoff, vol. vol. 5. pp. 345-358. Washington DC: National biomedical research foundation; 1978: 345-358.
46. Boyer RS, Moore JS: A fast string searching algorithm. Commun. ACM 1977, 20:762-772.
47. Stylos WA, Merryman CF, Maurer PH: Antigenicity of polypeptides (poly-alpha-amino acids). Distribution of sheep antibodies to polymers of alpha-L-amino acids of varying net electrical charge and lysozyme. Int Arch Allergy Appl Immunol 1970, 39:381-390.
48. Jasin HE, Glynn LE: The Antigenic Properties of Some Synthetic Poly-Iminoacids. Ii. The Antigenicity of Polypeptides Related to Collagen; Peptides Containing Hydroxyproline and Acetyl-Hydroxy-Proline. Immunology 1965, 32:260-269.
49. Watts TH, Sastry PA, Hodges RS, Paranchych W: Mapping of the antigenic determinants of Pseudomonas aeruginosa PAK polar pili. Infect Immun 1983, 42:113-121.
50. Fang CY, Chang YS, Chow KP, Yu JS, Chang HY: Construction and characterization of monoclonal antibodies specific to Epstein-Barr virus latent membrane protein 1. J Immunol Methods 2004, 287:21-30.
51. Plasterer TN: PROTEAN. Protein sequence analysis and prediction. Mol Biotech 2000, 16:117-126.
52. Boix E, Carreras E, Nikolovski Z, Cuchillo CM, Nogues MV: Identification and characterization of human eosinophil cationic protein by an epitope-specific antibody. J Leukoc Biol 2001, 69:1027-1035.
53. Leonidas DD, Shapiro R, Allen SC, Subbarao GV, Veluraja K, Acharya KR: Refined crystal structures of native human angiogenin and two active site variants: implications for the unique functional properties of an enzyme involved in neovascularisation during tumour growth. J Mol Biol 1999, 285:1209-1233.
54. Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim JH, Saito K, Sakamoto A, Inoue M, Shirouzu M, et al: Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 2002, 110:775-787.
55. Arumugam S, Van Doren SR: Global orientation of bound MMP-3 and N-TIMP-1 in solution via residual dipolar couplings. Biochemistry 2003, 42:7950-7958.
56. Hirose T, Patterson C, Pourmotabbed T, Mainardi CL, Hasty KA: Structure-function relationship of human neutrophil collagenase: identification of regions responsible for substrate specificity and general proteinase activity. Proc Natl Acad Sci U S A 1993, 90:2569-2573.
57. Arza B, De Maeyer M, Felez J, Collen D, Lijnen HR: Critical role of glutamic acid 202 in the enzymatic activity of stromelysin-1 (MMP-3). Eur J Biochem 2001, 268:826-831.
58. Wu JW, Krawitz AR, Chai J, Li W, Zhang F, Luo K, Shi Y: Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: insights on Ski-mediated repression of TGF-beta signaling. Cell 2002, 111:357-367.
59. Shi Y, Hata A, Lo RS, Massague J, Pavletich NP: A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature 1997, 388:87-93.
60. Qin B, Lam SS, Lin K: Crystal structure of a transcriptionally active Smad4 fragment. Structure Fold Des 1999, 7:1493-1503.
61. Zhang FH: Characterization of interaction region between caboxypeptidase E and human ribonuclease 3. Hsinchu: National Tsing Hua University; 2005. Master Thesis.
62. Wu CM, Chang HT, Chang MD: Membrane-bound carboxypeptidase E facilitates the entry of eosinophil cationic protein into neuroendocrine cells. Biochem J 2004, 382:841-848.
63. Younus H, Owais M, Rao DN, Saleemuddin M: Stabilization of pancreatic ribonuclease A by immobilization on Sepharose-linked antibodies that recognize the labile region of the enzyme. Biochim Biophys Acta 2001, 1548:114-120.
64. Chang G, Roth CB: Structure of MsbA from E. coli: a homolog of the multidrug resistance ATP binding cassette (ABC) transporters. Science 2001, 293:1793-1800.
65. Chang G: Structure of MsbA from Vibrio cholera: a multidrug resistance ABC transporter homolog in a closed conformation. J Mol Biol 2003, 330:419-430.
66. Kumar K, Brady M, Shapiro R: Selective abolition of pancreatic RNase binding to its inhibitor protein. Proc Natl Acad Sci U S A 2004, 101:53-58.
67. Sorimachi K, Jacks AJ, Le Gal-Coeffet MF, Williamson G, Archer DB, Williamson MP: Solution structure of the granular starch binding domain of glucoamylase from Aspergillus niger by nuclear magnetic resonance spectroscopy. J Mol Biol 1996, 259:970-987.
68. Korolkova YV, Tseng GN, Grishin EV: Unique interaction of scorpion toxins with the hERG channel. J Mol Recognit 2004, 17:209-217.
69. Kewley RJ, Whitelaw ML, Chapman-Smith A: The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. Int J Biochem Cell Biol 2004, 36:189-204.
70. Corbin JD, Francis SH: Cyclic GMP phosphodiesterase-5: target of sildenafil. J Biol Chem 1999, 274:13729-13732.
71. Houslay MD, Milligan G: Tailoring cAMP-signalling responses through isoform multiplicity. Trends Biochem Sci 1997, 22:217-224.
72. Houslay MD, Sullivan M, Bolger GB: The multienzyme PDE4 cyclic adenosine monophosphate-specific phosphodiesterase family: intracellular targeting, regulation, and selective inhibition by compounds exerting anti-inflammatory and antidepressant actions. Adv Pharmacol 1998, 44:225-342.
73. Manganiello VC, Taira M, Degerman E, Belfrage P: Type III cGMP-inhibited cyclic nucleotide phosphodiesterases (PDE3 gene family). Cell Signal 1995, 7:445-455.
74. Muller T, Engels P, Fozard JR: Subtypes of the type 4 cAMP phosphodiesterases: structure, regulation and selective inhibition. Trends Pharmacol Sci 1996, 17:294-298.
75. Thompson WJ: Cyclic nucleotide phosphodiesterases: pharmacology, biochemistry and function. Pharmacol Ther 1991, 51:13-33.
76. Torphy TJ: Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 1998, 157:351-370.
77. Zhao AZ, Yan C, Sonnenburg WK, Beavo JA: Recent advances in the study of Ca2+/CaM-activated phosphodiesterases: expression and physiological functions. Adv Second Messenger Phosphoprotein Res 1997, 31:237-251.
78. Houslay MD, Schafer P, Zhang KY: Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today 2005, 10:1503-1519.
79. Harlow E, Lane D: Antibodies: a laboratory manual. New York: Cold Spring Harbor Laboratory; 1988.
80. Maurer PH, Merryman CF, Stylos WA: Antigenicity of polypeptides (poly-alpha-amino acids). Distribution of sheep antibodies to dinitrinophenyl-(DNP) conjugates of polymers of alpha-L-amino acids of varying electrical charge. Int Arch Allergy Appl Immunol 1970, 39:435-444.
81. Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW, Jr., Leahy DJ: Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 2003, 421:756-760.
82. Wind T, Jensen MA, Andreasen PA: Epitope mapping for four monoclonal antibodies against human plasminogen activator inhibitor type-1: implications for antibody-mediated PAI-1-neutralization and vitronectin-binding. Eur J Biochem 2001, 268:1095-1106.
83. Tai PC, Spry CJ, Peterson C, Venge P, Olsson I: Monoclonal antibodies distinguish between storage and secreted forms of eosinophil cationic protein. Nature 1984, 309:182-184.
84. Rosenberg HF, Tiffany HL: Characterization of the eosinophil granule proteins recognized by the activation-specific antibody EG2. J Leukoc Biol 1994, 56:502-506.
85. Bailey TL, Gribskov M: The megaprior heuristic for discovering protein sequence patterns. Proc Int Conf Intell Syst Mol Biol 1996, 4:15-24.
86. Bailey TL, Elkan C: Fitting a mixture model by expectation maximization to discover motifs in biopolymers. In: The second International Conference on Intelligent Systems for Molecular Biology; 1994. 28-36.
87. Bailey TL, Gribskov M: Combining evidence using p-values: application to sequence homology searches. Bioinformatics 1998, 14:48-54.
88. Zhu H, Schein CH, Braun W: MASIA: recognition of common patterns and properties in multiple aligned protein sequences. Bioinformatics 2000, 16:950-951.
89. Sigrist CJ, Cerutti L, Hulo N, Gattiker A, Falquet L, Pagni M, Bairoch A, Bucher P: PROSITE: a documented database using patterns and profiles as motif descriptors. Brief Bioinform 2002, 3:265-274.
90. Subramanian S, Andal S, Karande AA, Radhakantha Adiga P: Epitope mapping and evaluation of specificity of T-helper sites in four major antigenic peptides of chicken riboflavin carrier protein in outbred rats. Biochem Biophys Res Commun 2003, 311:11-16.
91. Margalit H, Spouge JL, Cornette JL, Cease KB, Delisi C, Berzofsky JA: Prediction of immunodominant helper T cell antigenic sites from the primary sequence. J Immunol 1987, 138:2213-2229.
92. Rothbard JB, Taylor WR: A sequence pattern common to T cell epitopes. Embo J 1988, 7:93-100.
93. Sbai H, Mehta A, DeGroot AS: Use of T cell epitopes for vaccine development. Curr Drug Targets Infect Disord 2001, 1:303-313.
94. Sturniolo T, Bono E, Ding J, Raddrizzani L, Tuereci O, Sahin U, Braxenthaler M, Gallazzi F, Protti MP, Sinigaglia F, et al: Generation of tissue-specific and promiscuous HLA ligand databases using DNA microarrays and virtual HLA class II matrices. Nat Biotechnol 1999, 17:555-561.
95. De Groot AS, Jesdale BM, Szu E, Schafer JR, Chicz RM, Deocampo G: An interactive Web site providing major histocompatibility ligand predictions: application to HIV research. AIDS Res Hum Retroviruses 1997, 13:529-531.
96. Sette A, Sidney J: HLA supertypes and supermotifs: a functional perspective on HLA polymorphism. Curr Opin Immunol 1998, 10:478-482.
97. De Groot AS, Sbai H, Frost J, Saint-Aubin C, Chinai N, Martin W, Bosma A, Skowron G, Mayer KH: Designing HIV-1 vaccines to reflect viral diversity and the global context of HIV/AIDS. AIDScience 2001, 1:http://aidscience.com/Articles/aidscience002.htm.
98. Ecale Zhou CL, Zemla AT, Roe D, Young M, Lam M, Schoeniger JS, Balhorn R: Computational approaches for identification of conserved/unique binding pockets in the A chain of ricin. Bioinformatics 2005, 21:3089-3096.
99. Cho HS, Leahy DJ: Structure of the extracellular region of HER3 reveals an interdomain tether. Science 2002, 297:1330-1333.
100. Bouyain S, Longo PA, Li S, Ferguson KM, Leahy DJ: The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand. Proc Natl Acad Sci U S A 2005, 102:15024-15029.
101. Reverter D, Maskos K, Tan F, Skidgel RA, Bode W: Crystal structure of human carboxypeptidase M, a membrane-bound enzyme that regulates peptide hormone activity. J Mol Biol 2004, 338:257-269.
102. Wlodawer A, Sjolin L: Structure of ribonuclease A: results of joint neutron and X-ray refinement at 2.0-A resolution. Biochemistry 1983, 22:2720-2728.

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