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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 徐駿森(Chun-Hua Hsu) | |
| dc.contributor.author | Meng-Hsuan Lin | en |
| dc.contributor.author | 林孟萱 | zh_TW |
| dc.date.accessioned | 2021-06-17T08:32:50Z | - |
| dc.date.available | 2025-01-01 | |
| dc.date.copyright | 2021-02-22 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-01-27 | |
| dc.identifier.citation | 1 Hogenhout, S. A., Van der Hoorn, R. A., Terauchi, R. Kamoun, S. Emerging concepts in effector biology of plant-associated organisms. Mol Plant Microbe Interact 22, 115-122, doi:10.1094/MPMI-22-2-0115 (2009). 2 Mitchum, M. G. et al. Nematode effector proteins: an emerging paradigm of parasitism. New Phytol 199, 879-894, doi:10.1111/nph.12323 (2013). 3 Hewezi, T. Cellular Signaling Pathways and Posttranslational Modifications Mediated by Nematode Effector Proteins. Plant Physiol 169, 1018-1026, doi:10.1104/pp.15.00923 (2015). 4 Hunter, C. A. Sibley, L. D. Modulation of innate immunity by Toxoplasma gondii virulence effectors. Nat Rev Microbiol 10, 766-778, doi:10.1038/nrmicro2858 (2012). 5 Stergiopoulos, I. de Wit, P. J. Fungal effector proteins. Annu Rev Phytopathol 47, 233-263, doi:10.1146/annurev.phyto.112408.132637 (2009). 6 Rapisarda, C. Fronzes, R. Secretion Systems Used by Bacteria to Subvert Host Functions. Curr Issues Mol Biol 25, 1-42, doi:10.21775/cimb.025.001 (2018). 7 Schatz, M., Tong, P. B. V. Beaumelle, B. Unconventional secretion of viral proteins. Semin Cell Dev Biol 83, 8-11, doi:10.1016/j.semcdb.2018.03.008 (2018). 8 Jean Beltran, P. M., Federspiel, J. D., Sheng, X. Cristea, I. M. Proteomics and integrative omic approaches for understanding host-pathogen interactions and infectious diseases. Mol Syst Biol 13, 922, doi:10.15252/msb.20167062 (2017). 9 Citarelli, M., Teotia, S. Lamb, R. S. Evolutionary history of the poly(ADP-ribose) polymerase gene family in eukaryotes. BMC Evol Biol 10, 308, doi:10.1186/1471-2148-10-308 (2010). 10 Perina, D. et al. Distribution of protein poly(ADP-ribosyl)ation systems across all domains of life. DNA Repair (Amst) 23, 4-16, doi:10.1016/j.dnarep.2014.05.003 (2014). 11 Aravind, L., Zhang, D., de Souza, R. F., Anand, S. Iyer, L. M. The natural history of ADP-ribosyltransferases and the ADP-ribosylation system. Curr Top Microbiol Immunol 384, 3-32, doi:10.1007/82_2014_414 (2015). 12 Munnur, D. et al. Reversible ADP-ribosylation of RNA. Nucleic Acids Res 47, 5658-5669, doi:10.1093/nar/gkz305 (2019). 13 Munnur, D. Ahel, I. Reversible mono-ADP-ribosylation of DNA breaks. FEBS J 284, 4002-4016, doi:10.1111/febs.14297 (2017). 14 Catara, G., Corteggio, A., Valente, C., Grimaldi, G. Palazzo, L. Targeting ADP-ribosylation as an antimicrobial strategy. Biochem Pharmacol 167, 13-26, doi:10.1016/j.bcp.2019.06.001 (2019). 15 Kunze, F. A. Hottiger, M. O. Regulating Immunity via ADP-Ribosylation: Therapeutic Implications and Beyond. Trends Immunol 40, 159-173, doi:10.1016/j.it.2018.12.006 (2019). 16 Alhammad, Y. M. O. Fehr, A. R. The Viral Macrodomain Counters Host Antiviral ADP-Ribosylation. Viruses 12, doi:10.3390/v12040384 (2020). 17 Fehr, A. R. et al. The impact of PARPs and ADP-ribosylation on inflammation and host-pathogen interactions. Genes Dev 34, 341-359, doi:10.1101/gad.334425.119 (2020). 18 Mitchell, G. Isberg, R. R. Innate Immunity to Intracellular Pathogens: Balancing Microbial Elimination and Inflammation. Cell Host Microbe 22, 166-175, doi:10.1016/j.chom.2017.07.005 (2017). 19 Le Page, C., Sanceau, J., Drapier, J. C. Wietzerbin, J. Inhibitors of ADP-ribosylation impair inducible nitric oxide synthase gene transcription through inhibition of NF kappa B activation. Biochem Biophys Res Commun 243, 451-457, doi:10.1006/bbrc.1998.8113 (1998). 20 Yamada, T. et al. Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense. Nat Immunol 17, 687-694, doi:10.1038/ni.3422 (2016). 21 Guo, T. et al. ADP-ribosyltransferase PARP11 modulates the interferon antiviral response by mono-ADP-ribosylating the ubiquitin E3 ligase beta-TrCP. Nat Microbiol 4, 1872-1884, doi:10.1038/s41564-019-0428-3 (2019). 22 Schwerk, J. et al. RNA-binding protein isoforms ZAP-S and ZAP-L have distinct antiviral and immune resolution functions. Nat Immunol 20, 1610-1620, doi:10.1038/s41590-019-0527-6 (2019). 23 Hayakawa, S. et al. ZAPS is a potent stimulator of signaling mediated by the RNA helicase RIG-I during antiviral responses. Nat Immunol 12, 37-44, doi:10.1038/ni.1963 (2011). 24 Bohio, A. A. et al. c-Abl-Mediated Tyrosine Phosphorylation of PARP1 Is Crucial for Expression of Proinflammatory Genes. J Immunol 203, 1521-1531, doi:10.4049/jimmunol.1801616 (2019). 25 Hassa, P. O. et al. Acetylation of poly(ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-kappaB-dependent transcription. J Biol Chem 280, 40450-40464, doi:10.1074/jbc.M507553200 (2005). 26 Minotti, R., Andersson, A. Hottiger, M. O. ARTD1 Suppresses Interleukin 6 Expression by Repressing MLL1-Dependent Histone H3 Trimethylation. Mol Cell Biol 35, 3189-3199, doi:10.1128/MCB.00196-15 (2015). 27 Robertsen, B. The role of type I interferons in innate and adaptive immunity against viruses in Atlantic salmon. Dev Comp Immunol 80, 41-52, doi:10.1016/j.dci.2017.02.005 (2018). 28 Marazzi, I. Garcia-Sastre, A. Interference of viral effector proteins with chromatin, transcription, and the epigenome. Curr Opin Microbiol 26, 123-129, doi:10.1016/j.mib.2015.06.009 (2015). 29 Wu, D. et al. Viral effector protein manipulates host hormone signaling to attract insect vectors. Cell Res 27, 402-415, doi:10.1038/cr.2017.2 (2017). 30 Li, Z. et al. Herpes simplex virus requires poly(ADP-ribose) polymerase activity for efficient replication and induces extracellular signal-related kinase-dependent phosphorylation and ICP0-dependent nuclear localization of tankyrase 1. J Virol 86, 492-503, doi:10.1128/JVI.05897-11 (2012). 31 Child, S. J., Franke, C. A. Hruby, D. E. Inhibition of vaccinia virus replication by nicotinamide: evidence for ADP-ribosylation of viral proteins. Virus Res 9, 119-132 (1988). 32 Liu, L. et al. Resolution of the cellular proteome of the nucleocapsid protein from a highly pathogenic isolate of porcine reproductive and respiratory syndrome virus identifies PARP-1 as a cellular target whose interaction is critical for virus biology. Vet Microbiol 176, 109-119, doi:10.1016/j.vetmic.2014.11.023 (2015). 33 Nukuzuma, S. et al. Suppressive effect of PARP-1 inhibitor on JC virus replication in vitro. J Med Virol 85, 132-137, doi:10.1002/jmv.23443 (2013). 34 Kuny, C. V. Sullivan, C. S. Virus-Host Interactions and the ARTD/PARP Family of Enzymes. PLoS Pathog 12, e1005453, doi:10.1371/journal.ppat.1005453 (2016). 35 Nargi-Aizenman, J. L., Simbulan-Rosenthal, C. M., Kelly, T. A., Smulson, M. E. Griffin, D. E. Rapid activation of poly(ADP-ribose) polymerase contributes to Sindbis virus and staurosporine-induced apoptotic cell death. Virology 293, 164-171, doi:10.1006/viro.2001.1253 (2002). 36 Grady, S. L., Hwang, J., Vastag, L., Rabinowitz, J. D. Shenk, T. Herpes simplex virus 1 infection activates poly(ADP-ribose) polymerase and triggers the degradation of poly(ADP-ribose) glycohydrolase. J Virol 86, 8259-8268, doi:10.1128/JVI.00495-12 (2012). 37 Guo, X., Carroll, J. W., Macdonald, M. R., Goff, S. P. Gao, G. The zinc finger antiviral protein directly binds to specific viral mRNAs through the CCCH zinc finger motifs. J Virol 78, 12781-12787, doi:10.1128/JVI.78.23.12781-12787.2004 (2004). 38 Cummins, N. Badley, A. The TRAIL to viral pathogenesis: the good, the bad and the ugly. Curr Mol Med 9, 495-505 (2009). 39 Todorova, T., Bock, F. J. Chang, P. PARP13 regulates cellular mRNA post-transcriptionally and functions as a pro-apoptotic factor by destabilizing TRAILR4 transcript. Nat Commun 5, 5362, doi:10.1038/ncomms6362 (2014). 40 Liu, C. H., Zhou, L., Chen, G. Krug, R. M. Battle between influenza A virus and a newly identified antiviral activity of the PARP-containing ZAPL protein. Proc Natl Acad Sci U S A 112, 14048-14053, doi:10.1073/pnas.1509745112 (2015). 41 Butepage, M., Eckei, L., Verheugd, P. Luscher, B. Intracellular Mono-ADP-Ribosylation in Signaling and Disease. Cells 4, 569-595, doi:10.3390/cells4040569 (2015). 42 Atasheva, S., Akhrymuk, M., Frolova, E. I. Frolov, I. New PARP gene with an anti-alphavirus function. J Virol 86, 8147-8160, doi:10.1128/JVI.00733-12 (2012). 43 Goodier, J. L., Pereira, G. C., Cheung, L. E., Rose, R. J. Kazazian, H. H., Jr. The Broad-Spectrum Antiviral Protein ZAP Restricts Human Retrotransposition. PLoS Genet 11, e1005252, doi:10.1371/journal.pgen.1005252 (2015). 44 Atasheva, S., Frolova, E. I. Frolov, I. Interferon-stimulated poly(ADP-Ribose) polymerases are potent inhibitors of cellular translation and virus replication. J Virol 88, 2116-2130, doi:10.1128/JVI.03443-13 (2014). 45 Koyuncu, E. et al. Sirtuins are evolutionarily conserved viral restriction factors. MBio 5, doi:10.1128/mBio.02249-14 (2014). 46 Guo, T. et al. ADP-ribosyltransferase PARP11 modulates the interferon antiviral response by mono-ADP-ribosylating the ubiquitin E3 ligase beta-TrCP. Nat Microbiol, doi:10.1038/s41564-019-0428-3 (2019). 47 Posavec, M., Timinszky, G. Buschbeck, M. Macro domains as metabolite sensors on chromatin. Cell Mol Life Sci 70, 1509-1524, doi:10.1007/s00018-013-1294-4 (2013). 48 Till, S. Ladurner, A. G. Sensing NAD metabolites through macro domains. Front Biosci (Landmark Ed) 14, 3246-3258 (2009). 49 Abraham, R. et al. ADP-ribosyl-binding and hydrolase activities of the alphavirus nsP3 macrodomain are critical for initiation of virus replication. Proc Natl Acad Sci U S A 115, E10457-E10466, doi:10.1073/pnas.1812130115 (2018). 50 Li, C. et al. Viral Macro Domains Reverse Protein ADP-Ribosylation. J Virol 90, 8478-8486, doi:10.1128/JVI.00705-16 (2016). 51 Leung, A. K. L., McPherson, R. L. Griffin, D. E. Macrodomain ADP-ribosylhydrolase and the pathogenesis of infectious diseases. PLoS Pathog 14, e1006864, doi:10.1371/journal.ppat.1006864 (2018). 52 Mesquita, I. et al. Exploring NAD+ metabolism in host-pathogen interactions. Cell Mol Life Sci 73, 1225-1236, doi:10.1007/s00018-015-2119-4 (2016). 53 Singhal, A. Cheng, C. Y. Host NAD+ metabolism and infections: therapeutic implications. Int Immunol, doi:10.1093/intimm/dxy068 (2018). 54 Neuvonen, M. Ahola, T. Differential activities of cellular and viral macro domain proteins in binding of ADP-ribose metabolites. J Mol Biol 385, 212-225, doi:10.1016/j.jmb.2008.10.045 (2009). 55 Gibson, B. A. Kraus, W. L. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol 13, 411-424, doi:10.1038/nrm3376 (2012). 56 Thauer, R. K. Citric-acid cycle, 50 years on. Modifications and an alternative pathway in anaerobic bacteria. Eur J Biochem 176, 497-508 (1988). 57 de Figueiredo, L. F., Gossmann, T. I., Ziegler, M. Schuster, S. Pathway analysis of NAD+ metabolism. Biochem J 439, 341-348, doi:10.1042/BJ20110320 (2011). 58 Han, W., Li, X. Fu, X. The macro domain protein family: structure, functions, and their potential therapeutic implications. Mutat Res 727, 86-103, doi:10.1016/j.mrrev.2011.03.001 (2011). 59 Karras, G. I. et al. The macro domain is an ADP-ribose binding module. EMBO J 24, 1911-1920, doi:10.1038/sj.emboj.7600664 (2005). 60 Kilianski, A., Mielech, A. M., Deng, X. Baker, S. C. Assessing activity and inhibition of Middle East respiratory syndrome coronavirus papain-like and 3C-like proteases using luciferase-based biosensors. J Virol 87, 11955-11962, doi:10.1128/JVI.02105-13 (2013). 61 Yang, X. et al. Proteolytic processing, deubiquitinase and interferon antagonist activities of Middle East respiratory syndrome coronavirus papain-like protease. J Gen Virol 95, 614-626, doi:10.1099/vir.0.059014-0 (2014). 62 Saikatendu, K. S. et al. Structural basis of severe acute respiratory syndrome coronavirus ADP-ribose-1''-phosphate dephosphorylation by a conserved domain of nsP3. Structure 13, 1665-1675, doi:10.1016/j.str.2005.07.022 (2005). 63 Egloff, M. P. et al. Structural and functional basis for ADP-ribose and poly(ADP-ribose) binding by viral macro domains. J Virol 80, 8493-8502, doi:10.1128/JVI.00713-06 (2006). 64 Makrynitsa, G. I. et al. Conformational plasticity of the VEEV macro domain is important for binding of ADP-ribose. J Struct Biol 206, 119-127, doi:10.1016/j.jsb.2019.02.008 (2019). 65 Cho, C. C., Lin, M. H., Chuang, C. Y. Hsu, C. H. Macro Domain from Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Is an Efficient ADP-ribose Binding Module: CRYSTAL STRUCTURE AND BIOCHEMICAL STUDIES. J Biol Chem 291, 4894-4902, doi:10.1074/jbc.M115.700542 (2016). 66 Tsika, A. C. et al. Deciphering the Nucleotide and RNA Binding Selectivity of the Mayaro Virus Macro Domain. J Mol Biol 431, 2283-2297, doi:10.1016/j.jmb.2019.04.013 (2019). 67 Park, E. Griffin, D. E. The nsP3 macro domain is important for Sindbis virus replication in neurons and neurovirulence in mice. Virology 388, 305-314, doi:10.1016/j.virol.2009.03.031 (2009). 68 Eriksson, K. K., Cervantes-Barragan, L., Ludewig, B. Thiel, V. Mouse hepatitis virus liver pathology is dependent on ADP-ribose-1''-phosphatase, a viral function conserved in the alpha-like supergroup. J Virol 82, 12325-12334, doi:10.1128/JVI.02082-08 (2008). 69 Nan, Y. Zhang, Y. J. Molecular Biology and Infection of Hepatitis E Virus. Front Microbiol 7, 1419, doi:10.3389/fmicb.2016.01419 (2016). 70 Fehr, A. R. et al. The Conserved Coronavirus Macrodomain Promotes Virulence and Suppresses the Innate Immune Response during Severe Acute Respiratory Syndrome Coronavirus Infection. mBio 7, doi:10.1128/mBio.01721-16 (2016). 71 Kuri, T. et al. The ADP-ribose-1''-monophosphatase domains of severe acute respiratory syndrome coronavirus and human coronavirus 229E mediate resistance to antiviral interferon responses. J Gen Virol 92, 1899-1905, doi:10.1099/vir.0.031856-0 (2011). 72 Anang, S. et al. Identification of critical residues in Hepatitis E virus macro domain involved in its interaction with viral methyltransferase and ORF3 proteins. Sci Rep 6, 25133, doi:10.1038/srep25133 (2016). 73 Magden, J. et al. Virus-specific mRNA capping enzyme encoded by hepatitis E virus. J Virol 75, 6249-6255, doi:10.1128/JVI.75.14.6249-6255.2001 (2001). 74 Ding, Q. et al. Hepatitis E virus ORF3 is a functional ion channel required for release of infectious particles. Proc Natl Acad Sci U S A 114, 1147-1152, doi:10.1073/pnas.1614955114 (2017). 75 Lau, S. K. et al. Polyphyletic origin of MERS coronaviruses and isolation of a novel clade A strain from dromedary camels in the United Arab Emirates. Emerg Microbes Infect 5, e128, doi:10.1038/emi.2016.129 (2016). 76 Lei, J., Kusov, Y. Hilgenfeld, R. Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein. Antiviral Res 149, 58-74, doi:10.1016/j.antiviral.2017.11.001 (2018). 77 Bird, J. G. et al. Highly efficient 5' capping of mitochondrial RNA with NAD(+) and NADH by yeast and human mitochondrial RNA polymerase. Elife 7, doi:10.7554/eLife.42179 (2018). 78 Cahova, H., Winz, M. L., Hofer, K., Nubel, G. Jaschke, A. NAD captureSeq indicates NAD as a bacterial cap for a subset of regulatory RNAs. Nature 519, 374-377, doi:10.1038/nature14020 (2015). 79 Bird, J. G. et al. The mechanism of RNA 5' capping with NAD+, NADH and desphospho-CoA. Nature 535, 444-447, doi:10.1038/nature18622 (2016). 80 Walters, R. W. et al. Identification of NAD+ capped mRNAs in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 114, 480-485, doi:10.1073/pnas.1619369114 (2017). 81 Chen, Y. Guo, D. Molecular mechanisms of coronavirus RNA capping and methylation. Virol Sin 31, 3-11, doi:10.1007/s12250-016-3726-4 (2016). 82 Ramanathan, A., Robb, G. B. Chan, S. H. mRNA capping: biological functions and applications. Nucleic Acids Res 44, 7511-7526, doi:10.1093/nar/gkw551 (2016). 83 Ralph, R. et al. 2019-nCoV (Wuhan virus), a novel Coronavirus: human-to-human transmission, travel-related cases, and vaccine readiness. J Infect Dev Ctries 14, 3-17, doi:10.3855/jidc.12425 (2020). 84 Shanmugaraj, B., Malla, A. Phoolcharoen, W. Emergence of Novel Coronavirus 2019-nCoV: Need for Rapid Vaccine and Biologics Development. Pathogens 9, doi:10.3390/pathogens9020148 (2020). 85 Yu, P., Zhu, J., Zhang, Z., Han, Y. Huang, L. A familial cluster of infection associated with the 2019 novel coronavirus indicating potential person-to-person transmission during the incubation period. J Infect Dis, doi:10.1093/infdis/jiaa077 (2020). 86 Rothe, C. et al. Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. N Engl J Med 382, 970-971, doi:10.1056/NEJMc2001468 (2020). 87 Hanscheid, T., Valadas, E. Grobusch, M. P. Coronavirus 2019-nCoV: Is the genie already out of the bottle? Travel Med Infect Dis, 101577, doi:10.1016/j.tmaid.2020.101577 (2020). 88 Rodriguez-Morales, A. J., MacGregor, K., Kanagarajah, S., Patel, D. Schlagenhauf, P. Going global - Travel and the 2019 novel coronavirus. Travel Med Infect Dis 33, 101578, doi:10.1016/j.tmaid.2020.101578 (2020). 89 Maenz, M. et al. Ocular toxoplasmosis past, present and new aspects of an old disease. Prog Retin Eye Res 39, 77-106, doi:10.1016/j.preteyeres.2013.12.005 (2014). 90 Martin, S. Congenital toxoplasmosis. Neonatal Netw 20, 23-30, doi:10.1891/0730-0832.20.4.23 (2001). 91 Saadatnia, G. Golkar, M. A review on human toxoplasmosis. Scand J Infect Dis 44, 805-814, doi:10.3109/00365548.2012.693197 (2012). 92 Aleixo, A. L., Curi, A. L., Benchimol, E. I. Amendoeira, M. R. Toxoplasmic Retinochoroiditis: Clinical Characteristics and Visual Outcome in a Prospective Study. PLoS Negl Trop Dis 10, e0004685, doi:10.1371/journal.pntd.0004685 (2016). 93 Morjaria, S. et al. Toxoplasma Encephalitis in Atypical Hosts at an Academic Cancer Center. Open Forum Infect Dis 3, ofw070, doi:10.1093/ofid/ofw070 (2016). 94 Soheilian, M. et al. Randomized trial of intravitreal clindamycin and dexamethasone versus pyrimethamine, sulfadiazine, and prednisolone in treatment of ocular toxoplasmosis. Ophthalmology 118, 134-141, doi:10.1016/j.ophtha.2010.04.020 (2011). 95 Houdek, P. Puppet Master: Possible Influence of the ParasiteToxoplasma Gondiion Managers and Employees. Academy of Management Perspectives 31, 63-81, doi:10.5465/amp.2015.0163 (2017). 96 Barragan, A. Sibley, L. D. Migration of Toxoplasma gondii across biological barriers. Trends Microbiol 11, 426-430, doi:10.1016/s0966-842x(03)00205-1 (2003). 97 Olafsson, E. B. Barragan, A. The unicellular eukaryotic parasite Toxoplasma gondii hijacks the migration machinery of mononuclear phagocytes to promote its dissemination. Biol Cell, doi:10.1111/boc.202000005 (2020). 98 Sibley, L. D. Intracellular parasite invasion strategies. Science 304, 248-253, doi:10.1126/science.1094717 (2004). 99 Cabral, C. M. et al. Neurons are the Primary Target Cell for the Brain-Tropic Intracellular Parasite Toxoplasma gondii. PLoS Pathog 12, e1005447, doi:10.1371/journal.ppat.1005447 (2016). 100 Koshy, A. A. et al. Toxoplasma co-opts host cells it does not invade. PLoS Pathog 8, e1002825, doi:10.1371/journal.ppat.1002825 (2012). 101 Nishikawa, Y. et al. Toxoplasma gondii infection induces apoptosis in noninfected macrophages: role of nitric oxide and other soluble factors. Parasite Immunol 29, 375-385, doi:10.1111/j.1365-3024.2007.00956.x (2007). 102 Whitmarsh, R. J. et al. A critical role for SOCS3 in innate resistance to Toxoplasma gondii. Cell Host Microbe 10, 224-236, doi:10.1016/j.chom.2011.07.009 (2011). 103 Brunet, J. et al. Toxoplasma gondii exploits UHRF1 and induces host cell cycle arrest at G2 to enable its proliferation. Cell Microbiol 10, 908-920, doi:10.1111/j.1462-5822.2007.01093.x (2008). 104 Chang, S. et al. Toxoplasma gondii Rhoptry Protein ROP16 Mediates Partially SH-SY5Y Cells Apoptosis and Cell Cycle Arrest by Directing Ser15/37 Phosphorylation of p53. Int J Biol Sci 11, 1215-1225, doi:10.7150/ijbs.10516 (2015). 105 Bannai, H. et al. Overproduction of the pro-apoptotic molecule, programmed cell death 5, in Toxoplasma gondii leads to increased apoptosis of host macrophages. J Vet Med Sci 71, 1183-1189 (2009). 106 Gavrilescu, L. C. Denkers, E. Y. IFN-gamma overproduction and high level apoptosis are associated with high but not low virulence Toxoplasma gondii infection. J Immunol 167, 902-909 (2001). 107 Hakimi, M. A., Olias, P. Sibley, L. D. Toxoplasma Effectors Targeting Host Signaling and Transcription. Clin Microbiol Rev 30, 615-645, doi:10.1128/CMR.00005-17 (2017). 108 Bradley, P. J. Sibley, L. D. Rhoptries: an arsenal of secreted virulence factors. Curr Opin Microbiol 10, 582-587, doi:10.1016/j.mib.2007.09.013 (2007). 109 Hakansson, S., Charron, A. J. Sibley, L. D. Toxoplasma evacuoles: a two-step process of secretion and fusion forms the parasitophorous vacuole. EMBO J 20, 3132-3144, doi:10.1093/emboj/20.12.3132 (2001). 110 Soldati, D., Dubremetz, J. F. Lebrun, M. Microneme proteins: structural and functional requirements to promote adhesion and invasion by the apicomplexan parasite Toxoplasma gondii. Int J Parasitol 31, 1293-1302, doi:10.1016/s0020-7519(01)00257-0 (2001). 111 Huynh, M. H., Boulanger, M. J. Carruthers, V. B. A conserved apicomplexan microneme protein contributes to Toxoplasma gondii invasion and virulence. Infect Immun 82, 4358-4368, doi:10.1128/IAI.01877-14 (2014). 112 Mercier, C. Cesbron-Delauw, M. F. Toxoplasma secretory granules: one population or more? Trends Parasitol 31, 60-71, doi:10.1016/j.pt.2014.12.002 (2015). 113 Kemp, L. E., Yamamoto, M. Soldati-Favre, D. Subversion of host cellular functions by the apicomplexan parasites. FEMS Microbiol Rev 37, 607-631, doi:10.1111/1574-6976.12013 (2013). 114 Bannai, H. et al. Programmed Cell Death 5 from Toxoplasma gondii: a secreted molecule that exerts a pro-apoptotic effect on host cells. Mol Biochem Parasitol 159, 112-120, doi:10.1016/j.molbiopara.2008.02.012 (2008). 115 Ibrahim, H. M., Xuan, X. Nishikawa, Y. Toxoplasma gondii cyclophilin 18 regulates the proliferation and migration of murine macrophages and spleen cells. Clin Vaccine Immunol 17, 1322-1329, doi:10.1128/CVI.00128-10 (2010). 116 Aliberti, J. et al. Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells. Nat Immunol 4, 485-490, doi:10.1038/ni915 (2003). 117 Fischer, G. Chemical aspects of peptide bond isomerisation. Chem Soc Rev 29, 119-127, doi:DOI 10.1039/a803742f (2000). 118 Otwinowski, Z. Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Method Enzymol 276, 307-326, doi:Doi 10.1016/S0076-6879(97)76066-X (1997). 119 Bunkoczi, G. et al. Phaser.MRage: automated molecular replacement. Acta Crystallogr D Biol Crystallogr 69, 2276-2286, doi:10.1107/S0907444913022750 (2013). 120 Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr 66, 213-221, doi:10.1107/S0907444909052925 (2010). 121 Emsley, P., Lohkamp, B., Scott, W. G. Cowtan, K. Features and development of Coot. Acta Crystallogr D Biol Crystallogr 66, 486-501, doi:10.1107/S0907444910007493 (2010). 122 DeLano, W. L. PyMOL molecular viewer: Updates and refinements. Abstr Pap Am Chem S 238 (2009). 123 Popp, O. et al. Site-specific noncovalent interaction of the biopolymer poly(ADP-ribose) with the Werner syndrome protein regulates protein functions. ACS Chem Biol 8, 179-188, doi:10.1021/cb300363g (2013). 124 Van Der Spoel, D. et al. GROMACS: fast, flexible, and free. J Comput Chem 26, 1701-1718, doi:10.1002/jcc.20291 (2005). 125 van Gunsteren, W. F. Berendsen, H. J. C. Computer Simulation of Molecular Dynamics: Methodology, Applications, and Perspectives in Chemistry. Angewandte Chemie International Edition in English 29, 992-1023, doi:10.1002/anie.199009921 (1990). 126 Gasymov, O. K. Glasgow, B. J. ANS fluorescence: potential to augment the identification of the external binding sites of proteins. Biochim Biophys Acta 1774, 403-411, doi:10.1016/j.bbapap.2007.01.002 (2007). 127 Farmer, B. T., 2nd et al. Localizing the NADP+ binding site on the MurB enzyme by NMR. Nat Struct Biol 3, 995-997 (1996). 128 Masse, J. E. Keller, R. AutoLink: Automated sequential resonance assignment of biopolymers from NMR data by relative-hypothesis-prioritization-based simulated logic. J Magn Reson 174, 133-151, doi:10.1016/j.jmr.2005.01.017 (2005). 129 Malet, H. et al. The crystal structures of Chikungunya and Venezuelan equine encephalitis virus nsP3 macro domains define a conserved adenosine binding pocket. J Virol 83, 6534-6545, doi:10.1128/JVI.00189-09 (2009). 130 Haikarainen, T. Lehtio, L. Proximal ADP-ribose Hydrolysis in Trypanosomatids is Catalyzed by a Macrodomain. Sci Rep 6, 24213, doi:10.1038/srep24213 (2016). 131 Huang, Y. P., Cho, C. C., Chang, C. F. Hsu, C. H. NMR assignments of the macro domain from Middle East respiratory syndrome coronavirus (MERS-CoV). Biomol NMR Assign 10, 245-248, doi:10.1007/s12104-016-9676-9 (2016). 132 Eckei, L. et al. The conserved macrodomains of the non-structural proteins of Chikungunya virus and other pathogenic positive strand RNA viruses function as mono-ADP-ribosylhydrolases. Sci Rep 7, 41746, doi:10.1038/srep41746 (2017). 133 McPherson, R. L. et al. ADP-ribosylhydrolase activity of Chikungunya virus macrodomain is critical for virus replication and virulence. Proc Natl Acad Sci U S A 114, 1666-1671, doi:10.1073/pnas.1621485114 (2017). 134 Daugherty, M. D., Young, J. M., Kerns, J. A. Malik, H. S. Rapid evolution of PARP genes suggests a broad role for ADP-ribosylation in host-virus conflicts. PLoS Genet 10, e1004403, doi:10.1371/journal.pgen.1004403 (2014). 135 Staff, P. O. Correction: Correction: Mechanism of Inhibition of the Human Sirtuin Enzyme SIRT3 by Nicotinamide: Computational and Experimental Studies. PLoS One 10, e0138393, doi:10.1371/journal.pone.0138393 (2015). 136 Jin, L. et al. Crystal structures of human SIRT3 displaying substrate-induced conformational changes. J Biol Chem 284, 24394-24405, doi:10.1074/jbc.M109.014928 (2009). 137 Borra, M. T., Langer, M. R., Slama, J. T. Denu, J. M. Substrate specificity and kinetic mechanism of the Sir2 family of NAD+-dependent histone/protein deacetylases. Biochemistry 43, 9877-9887, doi:10.1021/bi049592e (2004). 138 Ran, Z., Rayet, B., Rommelaere, J. Faisst, S. Parvovirus H-1-induced cell death: influence of intracellular NAD consumption on the regulation of necrosis and apoptosis. Virus Res 65, 161-174 (1999). 139 Borra, M. T., Smith, B. C. Denu, J. M. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem 280, 17187-17195, doi:10.1074/jbc.M501250200 (2005). 140 Gertz, M. et al. A molecular mechanism for direct sirtuin activation by resveratrol. PLoS One 7, e49761, doi:10.1371/journal.pone.0049761 (2012). 141 Kaeberlein, M. et al. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem 280, 17038-17045, doi:10.1074/jbc.M500655200 (2005). 142 Lin, S. C. et al. Effective inhibition of MERS-CoV infection by resveratrol. BMC Infect Dis 17, 144, doi:10.1186/s12879-017-2253-8 (2017). 143 Canto, C., Sauve, A. A. Bai, P. Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes. Mol Aspects Med 34, 1168-1201, doi:10.1016/j.mam.2013.01.004 (2013). 144 Hay, S. Kannourakis, G. A time to kill: viral manipulation of the cell death program. J Gen Virol 83, 1547-1564, doi:10.1099/0022-1317-83-7-1547 (2002). 145 Alhammad, Y. M. O. et al. The SARS-CoV-2 conserved macrodomain is a highly efficient ADP-ribosylhydrolase enzyme. bioRxiv, doi:10.1101/2020.05.11.089375 (2020). 146 Frick, D. N., Virdi, R. S., Vuksanovic, N., Dahal, N. Silvaggi, N. R. Molecular Basis for ADP-Ribose Binding to the Mac1 Domain of SARS-CoV-2 nsp3. Biochemistry 59, 2608-2615, doi:10.1021/acs.biochem.0c00309 (2020). 147 Piotrowski, Y. et al. Crystal structures of the X-domains of a Group-1 and a Group-3 coronavirus reveal that ADP-ribose-binding may not be a conserved property. Protein Sci 18, 6-16, doi:10.1002/pro.15 (2009). 148 Laskowski, R. A. Swindells, M. B. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 51, 2778-2786, doi:10.1021/ci200227u (2011). 149 Guntert, P. Automated NMR structure calculation with CYANA. Methods Mol Biol 278, 353-378, doi:10.1385/1-59259-809-9:353 (2004). 150 Shen, Y., Delaglio, F., Cornilescu, G. Bax, A. TALOS+: a hybrid method for predicting protein backbone torsion angles from NMR chemical shifts. J Biomol NMR 44, 213-223, doi:10.1007/s10858-009-9333-z (2009). 151 Dalvit, C. et al. Identification of compounds with binding affinity to proteins via magnetization transfer from bulk water. J Biomol NMR 18, 65-68, doi:10.1023/a:1008354229396 (2000). 152 Raingeval, C. et al. 1D NMR WaterLOGSY as an efficient method for fragment-based lead discovery. J Enzyme Inhib Med Chem 34, 1218-1225, doi:10.1080/14756366.2019.1636235 (2019). 153 Hopkins, J. B., Gillilan, R. E. Skou, S. BioXTAS RAW: improvements to a free open-source program for small-angle X-ray scattering data reduction and analysis. J Appl Crystallogr 50, 1545-1553, doi:10.1107/S1600576717011438 (2017). 154 Markley, J. L. et al. Recommendations for the presentation of NMR structures of proteins and nucleic acids. IUPAC-IUBMB-IUPAB Inter-Union Task Group on the Standardization of Data Bases of Protein and Nucleic Acid Structures Determined by NMR Spectroscopy. J Biomol NMR 12, 1-23, doi:10.1023/a:1008290618449 (1998). 155 Louis-Jeune, C., Andrade-Navarro, M. A. Perez-Iratxeta, C. Prediction of protein secondary structure from circular dichroism using theoretically derived spectra. Proteins 80, 374-381, doi:10.1002/prot.23188 (2012). 156 Cooper, T. M. Woody, R. W. The effect of conformation on the CD of interacting helices: a theoretical study of tropomyosin. Biopolymers 30, 657-676, doi:10.1002/bip.360300703 (1990). 157 Sala, F. A., Valadares, N. F., Macedo, J. N., Borges, J. C. Garratt, R. C. Heterotypic Coiled-Coil Formation is Essential for the Correct Assembly of the Septin Heterofilament. Biophys J 111, 2608-2619, doi:10.1016/j.bpj.2016.10.032 (2016). 158 Judy, E. Kishore, N. A look back at the molten globule state of proteins: thermodynamic aspects. Biophys Rev 11, 365-375, doi:10.1007/s12551-019-00527-0 (2019). 159 Khan, M. K., Rahaman, H. Ahmad, F. Conformation and thermodynamic stability of pre-molten and molten globule states of mammalian cytochromes-c. Metallomics 3, 327-338, doi:10.1039/c0mt00078g (2011). 160 Arai, M. Kuwajima, K. Role of the molten globule state in protein folding. Adv Protein Chem 53, 209-282, doi:10.1016/s0065-3233(00)53005-8 (2000). 161 Huang, T. Y. et al. Structure of the Complex between a Heparan Sulfate Octasaccharide and Mycobacterial Heparin-Binding Hemagglutinin. Angew Chem Int Ed Engl 56, 4192-4196, doi:10.1002/anie.201612518 (2017). 162 Halonen, S. K. Weidner, E. Overcoating of Toxoplasma parasitophorous vacuoles with host cell vimentin type intermediate filaments. J Eukaryot Microbiol 41, 65-71, doi:10.1111/j.1550-7408.1994.tb05936.x (1994). 163 Zhou, D. H. et al. Modulation of mouse macrophage proteome induced by Toxoplasma gondii tachyzoites in vivo. Parasitol Res 109, 1637-1646, doi:10.1007/s00436-011-2435-z (2011). 164 He, C. et al. Host Cell Vimentin Restrains Toxoplasma gondii Invasion and Phosphorylation of Vimentin is Partially Regulated by Interaction with TgROP18. Int J Biol Sci 13, 1126-1137, doi:10.7150/ijbs.21247 (2017). 165 Xia, J. et al. Genome-Wide Bimolecular Fluorescence Complementation-Based Proteomic Analysis of Toxoplasma gondii ROP18's Human Interactome Shows Its Key Role in Regulation of Cell Immunity and Apoptosis. Front Immunol 9, 61, doi:10.3389/fimmu.2018.00061 (2018). 166 Musaelyan, A. et al. Vimentin as antigenic target in autoimmunity: A comprehensive review. Autoimmun Rev 17, 926-934, doi:10.1016/j.autrev.2018.04.004 (2018). 167 Du, N. et al. Cell surface vimentin is an attachment receptor for enterovirus 71. J Virol 88, 5816-5833, doi:10.1128/JVI.03826-13 (2014). 168 Schafer, G. et al. Vimentin Modulates Infectious Internalization of Human Papillomavirus 16 Pseudovirions. J Virol 91, doi:10.1128/JVI.00307-17 (2017). 169 Bastounis, E. E., Yeh, Y. T. Theriot, J. A. Matrix stiffness modulates infection of endothelial cells by Listeria monocytogenes via expression of cell surface vimentin. Mol Biol Cell 29, 1571-1589, doi | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74382 | - |
| dc.description.abstract | 病原體劫持了宿主的細胞功能，以便產生有利病原體生存和繁殖的環境。病原微生物，包括分類上屬於真核生物的寄生蟲，原核生物的細菌，甚至病毒都會表達效應蛋白質(Effector protein)。效應蛋白質通常由於通過增加病原體的入侵效率，抑制宿主的免疫系統或啟動病原體的複製，因而對病原體有利。 Macro domain 與涉及DNA 修復、轉錄和免疫反應的轉錄後修飾二磷酸腺苷核糖化（ADP-ribosylation）密切相關。積累至今的證據表示，病毒的macro domain 可透過與二磷酸腺苷核糖（ADP-ribose）分子或其他NAD 的代謝產物相互作用來調節宿主的二磷酸腺苷核糖化修飾。本研究對於MERS-CoV macro domain 與NAD代謝產物結合作用進行調查：透過各種生物物理學的實驗方法在室溫及人體溫度下測量中東呼吸道綜合症冠狀病毒(MERS-CoV)的macro domain 與各種NAD 代謝產物（包括ADP-ribose, NAD, ATP, ADP 和AMP）之間的交互作用。另外我們得到了這些NAD 代謝產物和MERS-CoV macro domain 的複合體晶體結構。藉此我們描述了各種NAD 代謝產物在結構中與蛋白質結合位之間的關係。並且透過核磁共振(NMR)化學位移擾動實驗鑑定了MERS-CoV macro domain 蛋白質結構中，與NAD 代謝物結合相關的關鍵胺基酸。另外，我們利用NMR 實驗方法捕捉MERSCoV macro domain 結合ADP-ribose 及NAD 的動態狀態。在人體溫度環境下，MERS-CoV macro domain 的受質結合區周圍具有彈性的無規則環圈(loop)區域的變化使蛋白質得以結合相較於ADP-ribose 而言具有更大化學結構的NAD。 自2019 年12 月以來，嚴重急性呼吸系統綜合症冠狀病毒2 (SARS-CoV-2)作為新的病原體引起大流行危機。由序列的保守性SARS-CoV-2 被發現表現一個macro domain，且此SARS-CoV-2 macro domain 可能具有影響人類細胞內的ADPribosylation的能力。我們驗證了SARS-CoV-2 macro domain 具有結合ADP-ribose多聚合體的功能，且具有可裂解單個ADP-ribose 的酵素活性。另外我們鑑定了SARS-CoV-2 macro domain 的蛋白質晶體結構。我們的研究提供了針對蛋白質結構，以生物物理和生物化學為基礎，進一步評估SARS-CoV-2 macro domain 與ADPribose結合作用在宿主細胞中的功能，且還可以做為未來設計新藥物的基礎。 弓形蟲病是由原生動物形態的寄生蟲弓形蟲感染所引起的全身性系統性疾病。弓形蟲病對於孕婦和免疫系統不全的人來說是危險的疾病。弓形蟲表現並分泌一種效應蛋白質稱為程序性細胞凋亡蛋白質5（TgPDCD5），會加強宿主細胞的細胞凋亡程度。儘管TgPDCD5 進入宿主細胞的詳細機制仍然未知，但是之前有人提出了一個簡約的論述：TgPDCD5 通過與細胞表面的肝素或硫酸乙醯肝素蛋白聚醣的交互作用，進而誘導胞吞作用而進入宿主細胞。我們的研究為TgPDCD5 的熔球狀特徵提供了確鑿的證據，並且解構了其NMR 水溶液結構，因此建立了TgPDCD5 與硫酸肝素多醣之間的交互作用的結構基礎。另外，在我們的研究中還描述了另一個弓形蟲表現並分泌的效應蛋白質Cyclophilin 18 (TgCyp18)所調節的TgPDCD5 的順反異構變化。相信我們針對TgPDCD5 與TgCyp18 的了解將為未來更近一步研究其功能提供依據。 我們對於MERS-CoV 及SARS-CoV-2 的macro domain 的研究，以及弓形蟲所表現分泌的TgPDCD5 和TgCyp18 的研究，將為病原體的效應蛋白質提供結構與功能方面的新見解。 | zh_TW |
| dc.description.abstract | Pathogens hijack host cellular function to generate an environment which beneficial to their perseverance and propagation. Pathogenic microorganisms, including eukaryotic parasites, prokaryotic bacteria and even viruses expressed effectors are proteins which advantages to the pathogens usually by increasing the invading efficiency, suppressing host immune system, or initiating the replication of pathogens. Macro domains are closely related to ADP-ribosylation, which involves in DNA repair, transcription, and immune response. Accumulated evidence indicated that viral macro domains regulated the host ADP-ribosylation by interacting with the ADP-ribose molecules or other NAD metabolites. Interactions between macro domain from Middle East Respiratory Syndrome coronavirus (MERS-CoV) and NAD metabolites, including ADP-ribose, NAD, ATP, ADP and AMP, were estimated by various biophysical approaches under room temperature and human body temperature. Crystal structures of these metabolites complexed MERS-CoV macro domains were determined. Details in the ligand binding sites of each solved NAD metabolites bound MERS-CoV macro domain were described. And, critical residues of MERS-CoV macro domain for NAD metabolites binding were identified by NMR chemical shift perturbation in solution. Furthermore, dynamic profiles of these interactions were also described. The flexible loops near ligand binding site of MERS-CoV macro domain generated a binding consequence of ligand with larger chemical structure than ADP-ribose, such as NAD, at 35°C. This study provided a systematical elucidation about the ligand binding behavior of MERS-CoV macro domain, especially at the human body temperature. Novel pathogen Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused pandemic crisis since December of 2019. SARS-CoV-2 encodes a conserved macro domain which may reverse cellular ADP-ribosylation. The macro domain of SARS-CoV-2 was examined as a poly-ADPR binding module and possesses mono-ADPR cleavage enzyme activity. Furthermore, crystal structure of SARS-CoV-2 macro domain was determined. Our study provides structural, biophysical and biochemical bases to further evaluate the role of the SARS-CoV-2 macro domain in the host response via ADP-ribose binding but also as a potential target for drug design against new disease. Toxoplasmosis is a systematic disease triggered by infection from protozoan parasite Toxoplasma gondii (T. gondii). This disease can be dangerous for pregnant women and people with compromised immune systems. T. gondii possess an effector protein, programmed cell death protein 5 (TgPDCD5), which involved in host cellular apoptosis enhancement. Although the mechanism of the entry of TgPDCD5 into host cell remained mysterious, a parsimonious suspicion was proposed before which about endocytosis inducing by interaction to extracellular matrixes such as heparin/heparan sulfate proteoglycans. Our research offered solid evidences about the molten globular feature of TgPDCD5 and characterized its solution structure. The structural basis of the interaction between TgPDCD5 and polysaccharide heparin sulfate was revealed. Furthermore, the TgPDCD5 cis/trans-isomerization regulating from another T. gondii effector protein Cyclophilin 18 (TgCyp18) was also described in our study. We believe our pilot elucidation about TgPDCD5 and TgCyp18 will provide the ground of further investigation about their function. Our studies about viral macro domains from MERS-CoV and SARS-CoV-2, furthermore about T. gondii secreted TgPDCD5 and TgCyp18, will provide new insights into the structure and function of these effector proteins from pathogens. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T08:32:50Z (GMT). No. of bitstreams: 1 U0001-2101202116015100.pdf: 65881377 bytes, checksum: 1b17e71039950f4ad111476eb67bcf25 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | 目錄 中文摘要. p9 ABSTRACT. p11 1. INTRODUCTION. p14 1.1 EFFECTOR PROTEINS. p14 PART I. VIRAL EFFECTOR PROTEINS: MACRO DOMAINS FROM MERS-COV AND SARS-COV-2. p17 1.2 ADP-ribosylation. p19 1.3 ADP-ribosylation involved in the innate immune response. p23 1.4 Viral macro domains regulating the host ADP-ribosylation. p28 1.5 NAD metabolites and ADP-ribosylation. p29 1.6. The viral macro domains. p30 1.7 The macro domain from two major pathogenic coronaviruses, MERSCoV and SARS-CoV-2. p30 PART II. EFFECTOR PROTEINS FROM TOXOPLASMA GONDII: PDCD5 AND CYCLOPHILIN 18. p34 1.8.1 Toxoplasma gondii, an intracellular pathogen. p34 1.8.2 Two effector proteins from Toxoplasma gondii: Programmed cellular death protein 5 and cyclophilin 18. p37 1.9 AIMS OF THIS STUDY. p42 PART I. VIRAL EFFECTOR PROTEINS: MACRO DOMAINS FROM MERSCOV AND SARS-COV-2. p44 2 MATERIALS AND METHODS. p45 2.1 METHODS FOR STUDYING VIRAL MACRO DOMAINS FROM MERS-COV AND SARS-COV-2. p45 2.1.1 PROTEIN EXPRESSION AND PURIFICATION. p45 2.1.2 CRYSTALLIZATION AND DATA COLLECTION. p46 2.1.3 STRUCTURE DETERMINATION AND REFINEMENT. p47 2.1.4 CIRCULAR DICHROISM (CD) SPECTROSCOPY. p48 2.1.5 DIFFERENTIAL SCANNING FLUORIMETRY. p48 2.1.6 LABEL-FREE DIFFERENTIAL SCANNING FLUORIMETRY (NANODSF). p49 2.1.7 ISOTHERMAL TITRATION CALORIMETRY. p49 2.1.8 DEMARYLATION ACTIVITY ASSAY. p50 2.1.9 POLY ADPR (PAR) BINDING ASSAY. p51 2.1.10 MOLECULAR DYNAMICS (MD) SIMULATIONS. p52 2.1.11 ANS FLUORESCENCE EXPERIMENT. p53 2.1.12 NMR SPECTROSCOPY AND CHEMICAL SHIFT PERTURBATION. p54 2.1.13 NMR RELAXATION ANALYSES. p55 2.1.14 NMR-BASED HIGH THROUGHPUT PRE-DRUG FRAGMENT SCREENING. p55 3 RESULTS AND DISCUSSIONS. p56 3.1 MERS-COV MACRO DOMAIN. p56 3.1.1 Evaluation of MERS-CoV macro domain binding with various NAD metabolites. p56 3.1.2 Coordination of NAD metabolites in MERS-CoV macro domain. p57 3.1.3 Identification of critical residues and binding ability of MERS-CoV macro domain by nuclear magnetic resonance (NMR) and isothermal titration calorimetry (ITC) titrations. p60 3.1.4 Binding behavior of NAD metabolites at physiological temperature. p62 3.1.5 De-MARylation of MERS-CoV macro domain at different temperatures. p66 3.1.6 Loops surrounding the ligand-binding site represent a tunable pocket. p68 3.1.7 Discussion. p71 3.2 SARS-COV-2 MACRO DOMAIN. p78 3.2.1 ADPR binding ability of the SARS-CoV-2 macro domain. p78 3.2.2 Enzyme activity of de-mono-ADP-ribosylation. p80 3.2.3 Poly-ADP-ribose (PAR) binding ability. p80 3.2.4 Overall structure of the SARS-CoV-2 macro domain in complex with ADPR. p81 3.2.5 Structural comparison of viral macro domains. p84 3.2.6 NMR assignments of the macro domain from SARS-CoV-2. p88 3.2.7 Primary pre-drug fragments screening. p89 PART II. EFFECTOR PROTEINS FROM TOXOPLASMA GONDII: PDCD5 AND CYCLOPHILIN 18. p91 4.1 METHODS USED FOR STUDYING TGPDCD5 AND TGCYP18. p92 4.1.1 PROTEIN EXPRESSION AND PURIFICATION. p92 4.1.2 CIRCULAR DICHROISM (CD). p94 4.1.3 SMALL ANGLED X-RAY SCATTERING (SAXS). p94 4.1.4 FLUORESCENCE SPECTROSCOPY. p95 4.1.5 HIGH-FIELD SOLUTION NUCLEAR MAGNETIC RESONANCE (NMR). p95 4.1.6 ISOTHERMAL TITRATION CALORIMETRY (ITC). p96 4.1.7 FLOW CYTOMETRY. p96 4.1.8 FLUORESCENCE POLARIZATION ASSAY. p97 4.1.9 COIMMUNOPRECIPITATION AND LC-MS/MS ANALYSIS. p98 5 RESULTS AND DISCUSSIONS. p99 5.1 TgPDCD5 as a molten globular protein. p99 5.2 The overall solution structure of TgPDCD5. p101 5.3 The loosely packed hydrophobic core of TgPDCD5. p104 5.4 The Interactions of TgPDCD5 with polysaccharides heparin sulfate and Enoxaparin. p106 5.5 Critical residues for Enoxaparin binding. p108 5.6 TgCyp18 regulating the Enoxaparin interaction of TgPDCD5 via the enzyme activity for peptidyl-prolyl cis/trans isomerization. p110 5.7 Identification of the TgPDCD5 binding proteins in human cell U937. p112 6 CONCLUSION. p116 PART I.1. MERS-COV MACRO DOMAIN. p116 PART I.2. SARS-COV-2 MACRO DOMAIN. p117 PART II. TGPDCD5 AND TGCYP18 FROM TOXOPLASMA GONDII. p118 FIGURES. p119 FIGURE 1. PURIFICATION OF MERS-COV MACRO DOMAIN. p120 FIGURE 2. EVALUATION OF MERS-COV MACRO DOMAIN BINDING WITH NAD METABOLITES BY TM VALUES. p121 FIGURE 3. NAD METABOLITES BINDING TO MERS-COV MACRO DOMAIN, AS PROBED VIA DIFFERENTIAL SCANNING FLUORIMETRY (DSF). p122 FIGURE 4. STEREO DIAGRAMS OF NAD METABOLITES BOUND IN MERS-COV MACRO DOMAIN LIGAND BINDING SITE WITH 2FO-FC ELECTRON DENSITY MAP CONTOURED AT 1.0 Å. p123 FIGURE 5. TWO DIVERGENCES BETWEEN THE FIVE STRUCTURES OF THE MERS-COV MACRO DOMAIN IN COMPLEX WITH DIFFERENT NAD METABOLITES. p124 FIGURE 6. INTERACTION OF MERS-COV MACRO DOMAIN WITH NAD METABOLITES. p125 FIGURE 7. THE LIGAND BINDING SITE OF MERS-COV MACRO DOMAIN CONSTRUCTED BY THREE REGIONS. p126 FIGURE 8. LIGPLOT+ DIAGRAMS FOR NAD METABOLITES COORDINATED WITH THE MERS-COV MACRO DOMAIN. p127 FIGURE 9. NMR PERTURBATION OF MERS-COV MACRO DOMAIN TITRATED WITH VARIOUS NAD METABOLITES AT 298K (A) AND 308K (B). p129 FIGURE 10. CHEMICAL SHIFT DIFFERENCE PER RESIDUE PLOT AT 298K (A) AND 308K (B). p130 FIGURE 11. MAPPING OF NAD METABOLITES BINDING SITES BY CHEMICAL SHIFT DIFFERENCE-BASED NMR. p131 FIGURE 12. ITC ANALYSIS OF MERS-COV MACRO DOMAIN WITH DIFFERENT NAD ANALOGUES AT 298K AND 308K. p133 FIGURE 13. CHEMICAL SHIFT PERTURBATIONS OF RESIDUES IN THREE REGIONS OF LIGAND BINDING SITE AT 308K. p134 FIGURE 14. POINT MUTATIONS AT DISTINGUISHED LOOPS 1 AND 2. p135 FIGURE 15. DE-MARYLATION OF THE MERS-COV MACRO DOMAIN AT DIFFERENT TEMPERATURES. p137 FIGURE 16. A TUNABLE LIGAND-BINDING SITE OF THE MERS-COV MACRO DOMAIN. p139 FIGURE 17. REDUCED SPECTRAL DENSITY VALUES OF THE MERS-COV MACRO DOMAIN. p140 FIGURE 18. TEMPERATURE TUNE OF APO FORM MERS-COV MACRO DOMAIN. p141 FIGURE 19. PURIFICATION OF SARS-COV-2 MACRO DOMAIN. p142 FIGURE 20. CIRCULAR DICHROISM (CD) SPECTRA ANALYSIS OF THE SARS-COV-2 MACRO DOMAIN. p143 FIGURE 21. ADPR BINDING OF THE SARS-COV-2 MACRO DOMAIN. p145 FIGURE 22. THERMAL SHIFT ASSAYS TO SARS-COV-2 MACRO DOMAIN. p146 FIGURE 23. FUNCTIONS OF THE SARS-COV-2 MACRO DOMAIN. p147 FIGURE 24. STRUCTURE OF THE SARS-COV-2 MACRO DOMAIN. p149 FIGURE 25. EVENTS DURING CRYSTALLIZATION TO OBTAIN ADPR COMPLEXED SARS-COV-2 MACRO DOMAIN. p151 FIGURE 26. LIGAND BINDING SITE OF VIRUS MACRO DOMAINS. p153 FIGURE 27. STRUCTURAL COMPARISON BETWEEN APO FORM AND ADPR-BOUND FORM OF THE SARS-COV-2 MACRO DOMAIN. p156 FIGURE 28. INTERACTIONS BETWEEN VIRAL MACRO DOMAINS AND ADPR. p157 FIGURE 29. MERS-COV MACRO DOMAIN-MIMICS MUTAGENESIS INTRODUCED INTO THE SARS-COV-2 MACRO DOMAIN. p159 FIGURE 30. 1H-15N HSQC SPECTRUM OF SARS-COV-2 MACRO DOMAIN. p160 FIGURE 31. THE SECONDARY STRUCTURE OF SARS-COV-2 MACRO DOMAIN IS PREDICTED BY CΑCΒ CHEMICAL SHIFT DIFFERENCE, AND TALOS+. p161 FIGURE 32. EXAMPLE OF WATERLOGSY SPECTRA FOR HIT COMPOUND 1. p162 FIGURE 33. VALIDATION OF THE FRAGMENT LIBRARY BY NMR CHEMICAL SHIFT PERTURBATION ASSAY AND DSF ASSAY. p164 FIGURE 34. PURIFICATION OF TGPDCD5. p165 FIGURE 35. CD SPECTRA OF TGPDCD5 WT. p166 FIGURE 36. MOLTEN GLOBULAR BEHAVIOR OF TGPDCD5. p167 FIGURE 37. THE SAXS PROFILE OF TGPDCD5 WT AND TRUNCATION 45-100. p169 FIGURE 38. PROFILE AT THE RANGE OF ANS-FLUORESCENCE ASSAY OF TGPDCD5 WT. p170 FIGURE 39. BACKBONE AMIDE AND SIDE CHAIN ASSIGNMENTS OF TGPDCD5 WT. p171 FIGURE 40. SOLUTION STRUCTURE OF TGPDCD5 WT. p173 FIGURE 41. STRIP PLOT FROM THE 15N-NOESY-HSQC OF RESIDUES I40 AND L81. p174 FIGURE 42. SEQUENCE ALIGNMENT OF PDCD5 PROTEINS FROM PATHOGENIC APICOMPLEXAN. p175 FIGURE 43. NMR DYNAMICS INFORMATION FOR TGPDCD5 WT. p176 FIGURE 44. U937 CELL VIABILITY MEASURED BY MTT ASSAY. p177 FIGURE 45. APOPTOSIS INDUCEMENT BY EACH FRAGMENT OF TGPDCD5. p178 FIGURE 46. THE INTERACTION BETWEEN HEPARIN SULFATE AND TGPDCD5 WT MONITORED BY ITC. p179 FIGURE 47. INTERACTION WITH HEPARIN SULFATE DETERMINED BY NMR. p181 FIGURE 48. ENOXAPARIN BINDING DETERMINED BY ITC. p182 FIGURE 49. INTERACTIONS WITH ENOXAPARIN DETERMINED BY NMR. p184 FIGURE 50. CRITICAL RESIDUES INVOLVED IN ENOXAPARIN BINDING. p185 FIGURE 51. ILLUSTRATION OF TGPDCD5 MUTATION DESIGNS. p186 FIGURE 52. ENOXAPARIN TITRATIONS TO TGPDCD5 MUTANTS. p187 FIGURE 53. PURIFICATION OF TGCYP18. p189 FIGURE 54. THE INTERACTION BETWEEN TGPDCD5 PEPTIDES AND TGCYP18 DETERMINED BY FLUORESCENCE POLARIZATION EXPERIMENTS. p190 FIGURE 55. THE ASSIGNMENT OF THE 1H-1H ROCSY SPECTRUM AT 298K OF CTERMINAL PEPTIDE FROM TGPDCD5 (104KNTPKVTM111). p191 FIGURE 56. TGCYP18 CATALYSIS OF THE CIS/TRANS-ISOMERIZATION OF CTERMINAL PEPTIDE OF TGPDCD5. p192 FIGURE 57. THE ENOXAPARIN TITRATION OF TGPDCD5 P107A. p193 FIGURE 58. COIMMUNOPRECIPITATION FOR LC-MS/MS ANALYSIS IDENTIFIED TGPDCD5-INTERACTING PROTEINS IN HUMAN U937 CELL. p195 TABLES. p196 TABLE 1. DATA COLLECTION AND REFINEMENT STATISTICS OF MERS-COV MACRO DOMAIN NAD METABOLITES BOUND FORMS. p197 TABLE 2. DATA COLLECTION AND REFINEMENT STATISTICS OF SARS-COV-2 MACRO DOMAIN IN COMPLEX WITH ADP-RIBOSE. p198 TABLE 3. MELTING TEMPERATURE (°C) OF THE MERS-COV MACRO DOMAIN APO FORM AND ADDED WITH VARIOUS NAD METABOLITES DETERMINED BY TWO ASSAYS, DSF AND CD. p199 TABLE 4. ITC BINDING ASSAYS OF INTERACTIONS BETWEEN NAD METABOLITES AND MERS-COV MACRO DOMAIN. p200 TABLE 5. THERMAL-DYNAMIC PARAMETERS FOR BINDING OF ADP-RIBOSE IN CORONAVIRUS (COV) MACRO DOMAINS. p201 TABLE 6 SUMMARY OF FRAGMENT-HITS OF SARS-COV-2 MACRO DOMAIN. p202 TABLE 7. RESTRAINTS AND STRUCTURE STATISTICS FOR 20 LOWEST ENERGY CONFORMERS OF TGPDCD5WT. p204 TABLE 8. SUMMARY OF TOP 23 TGPDCD5 PROTEIN-PROTEIN INTERACTION PARTNERS IN HUMAN CELL U937 IDENTIFIED BY LC-MS/MS. p205 Table 9. Recombinant TgPDCD5WT resonance assignments at pH 4.5 and 310K. p208 REFERENCES. p217 | |
| dc.language.iso | zh-TW | |
| dc.title | 病原體效應蛋白質之結構和功能解析：冠狀病毒之Macro domains及弓形蟲之宿主調控蛋白質PDCD5與Cyclophilin 18 | zh_TW |
| dc.title | Structural and functional elucidations of pathogens effector proteins: Macro domains from coronaviruses and host regulated protein PDCD5 and Cyclophilin 18 from Toxoplasma gondii | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 109-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 陳金榜(Chinpan Chen),詹迺立(Nei-li Chan),蘇士哲(Shih-Che Sue),陳慧文(Hui-Wen Chen),譚賢明(Bertrand Tan) | |
| dc.subject.keyword | 中東呼吸道綜合症冠狀病毒,嚴重急性呼吸系統綜合症冠狀病毒2,病毒macro domain,二磷酸腺苷核糖化修飾,弓形蟲,弓形蟲PDCD5,弓形蟲 Cyp18,熔球態蛋白質,硫酸肝素多醣交互作用,晶體結構,核磁共振水溶液結構,生物物理,生物化學, | zh_TW |
| dc.subject.keyword | viral macro domain,MERS-CoV,SARS-CoV-2,ADP-ribosylation,Toxoplasma gondii,molten globule,PDCD5,Cyp18,heparin sulfate binding,X-ray crystal structure,NMR structure in solution,biophysics,biochemistry, | en |
| dc.relation.page | 275 | |
| dc.identifier.doi | 10.6342/NTU202100116 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2021-01-28 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 基因體與系統生物學學位學程 | zh_TW |
| 顯示於系所單位： | 基因體與系統生物學學位學程 | |
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