Insights into the Initiation of JC Virus DNA Replication Derived from the Crystal Structure of the T-Antigen Origin Binding Domain


JC virus is a member of the Polyomavirus family of DNA tumor viruses and the causative agent of progressive multifocal leukoencephalopathy (PML). PML is a disease that occurs primarily in people who are immunocompromised and is usually fatal. As with other Polyomavirus family members, the replication of JC virus (JCV) DNA is dependent upon the virally encoded protein T-antigen. To further our understanding of JCV replication, we have determined the crystal structure of the origin-binding domain (OBD) of JCV T-antigen. This structure provides the first molecular understanding of JCV T-ag replication functions; for example, it suggests how the JCV T-ag OBD site-specifically binds to the major groove of GAGGC sequences in the origin. Furthermore, these studies suggest how the JCV OBDs interact during subsequent oligomerization events. We also report that the OBD contains a novel “pocket”; which sequesters the A1 & B2 loops of neighboring molecules. Mutagenesis of a residue in the pocket associated with the JCV T-ag OBD interfered with viral replication. Finally, we report that relative to the SV40 OBD, the surface of the JCV OBD contains one hemisphere that is highly conserved and one that is highly variable.


Vyšlo v časopise: Insights into the Initiation of JC Virus DNA Replication Derived from the Crystal Structure of the T-Antigen Origin Binding Domain. PLoS Pathog 10(2): e32767. doi:10.1371/journal.ppat.1003966
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003966

Souhrn

JC virus is a member of the Polyomavirus family of DNA tumor viruses and the causative agent of progressive multifocal leukoencephalopathy (PML). PML is a disease that occurs primarily in people who are immunocompromised and is usually fatal. As with other Polyomavirus family members, the replication of JC virus (JCV) DNA is dependent upon the virally encoded protein T-antigen. To further our understanding of JCV replication, we have determined the crystal structure of the origin-binding domain (OBD) of JCV T-antigen. This structure provides the first molecular understanding of JCV T-ag replication functions; for example, it suggests how the JCV T-ag OBD site-specifically binds to the major groove of GAGGC sequences in the origin. Furthermore, these studies suggest how the JCV OBDs interact during subsequent oligomerization events. We also report that the OBD contains a novel “pocket”; which sequesters the A1 & B2 loops of neighboring molecules. Mutagenesis of a residue in the pocket associated with the JCV T-ag OBD interfered with viral replication. Finally, we report that relative to the SV40 OBD, the surface of the JCV OBD contains one hemisphere that is highly conserved and one that is highly variable.


Zdroje

1. EhlersB, WielandU (2013) The novel human polyomaviruses HPyV6, 7, 9 and beyond. APMIS DOI10.1111: 1–13.

2. ScudaN, MadindaNF, Akoua-KoffiC, AdjogousEV, WeversD, et al. (2013) Novel Polyomaviruses of Nonhuman Primates: Genetic and Serological Predictors for the Existence of Multiple Unknown Polyomaviruses within the Human Population. PLoS Pathogens 9: e1003429.

3. Fanning E, Pipas JM (2009) Polyomavirus DNA Replication and Role in Disease. In: DePamphilis M, editor. DNA Replication and Human Disease: Cold Spring Harbor Monograph Archive. pp. 627–644.

4. JiangM, AbendJR, JohsonSF, ImperialeMJ (2009) The Role of Polyomaviruses in Human Disease. Virology 384: 266–273.

5. WhiteMK, GordonJ, KhaliliK (2013) The Rapidly Expanding Family of Human Polyomaviruses: Recent Developments in Understanding Their Life Cycle and Role in Human Pathology. PLOS Pathogens 9: e1003206.

6. BrewBJ, DaviesNWS, CinqueP, CliffordDB, NathA (2010) Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nature Reviews Neurology 6: 667–679.

7. BellizziA, AnzivinoE, RodioDM, PalamaraAT, NencioniL, et al. (2013) New Insights on Human Polyomavirus JC and Pathogenesis of Progressive Multifocal Leukoencephalopathy. Clinical and Developmental Immunology 2013

8. FerenczyMW, MarshallLJ, NelsonCDS, AtwoodWJ, NathA, et al. (2012) Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Deymelinating Disease of the Human Brain. Clinical Microbiology Reviews 25: 471–506.

9. PadgettBL, WalkerDL, ZurheinGM, VarakisJN (1977) Differential neurooncogenicity of strains of JC virus, a hyman polyoma virus, in newborn Syrian hamsters. Cancer Research 37: 718–720.

10. WalkerDL, PadgettBL (1983) Progressive multifocal leukoencephalopathy. Comprehensive Virology 18: 161–193.

11. BergerJR, KaszovitzB, PostMJ, DickinsonG (1987) Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. A review of the literature with a report of sixteen cases. . Annals Intern Med 107: 78–87.

12. PowerC, GladdenJG, HallidayW (2000) AIDS and non-AIDS related PML association with distinct p53 polymorphism. Neurology 54: 743–746.

13. KeanJM, RaoS, WangM, GarciaRL (2009) Seroepidemiology of human polyomaviruses. PLoS Pathogens 5: e1000363.

14. KoralnikIJ (2013) Progressive Multifocal Leukoencephalopathy Revisited: Has the Disease Outgrown Its Name? Annals of Neurology 60: 162–173.

15. WarnkeC, MengeT, hartungH-P, RackeMK (2010) Natalizumab and Progressive Multifocal Leukoencephalopathy. Arch Neurol 67: 923–930.

16. Del ValleL, WhiteMK, KhaliliK (2008) Potential Mechanisms of the Human Polyomavirus JC in Neural Oncogenesis. J Neuropathol Exp Neurol 67: 729–740.

17. MaginnisMS, AtwoodWJ (2009) JC Virus: An oncogenic virus in animals and humans? Seminars in Cancer Biology 19: 261–269.

18. LynchKJ, FrisqueRJ (1990) Identification of Critical Elements within the JC Virus DNA Replication Origin. Journal of Virology 64: 5812–5822.

19. SockE, WegnerM, GrummtF (1993) Large T-antigen and sequences within the regulatory region of JC virus both contribute to the features of JC virus DNA replication. Virology 197: 537–548.

20. GosertR, KardasP, MajorEO, HirschHH (2010) Rearranged JC Virus Noncoding Control Regions Found in Progressive Multifocal Leukoencephalopathy Patient Samples Increases Virus Early Gene Expression and Replication Rates. Journal of Virology 84: 10448–10456.

21. ChangC-F, TadaH, KahaliliK (1994) The role of a pentanucleotide repeat sequence, AGGGAAGGA, in the regulation of JC virus DNA replication. Gene 148: 309–314.

22. FrisqueRJ (1983) Nucleotide sequence of the region encompassing the JC virus origin of DNA replication. J of Virology 46: 170–176.

23. TavisJE, FrisqueRJ (1991) Altered DNA Binding and Replication Activities of JC Virus T-Antigen Mutants. Virology 183: 239–250.

24. LynchKJ, FrisqueRJ (1991) Factors contributing to the restricted DNA replicating activity of JC virus. Virology 180: 306–317.

25. AnP, Saenz RoblesMT, PipasJM (2012) Large T Antigens of Polyomaviruses: Amazing Molecular Machines. Annu Rev Microbiol 66: 213–236.

26. FanningE, KnippersR (1992) Structure and function of simian virus 40 large tumor antigen. Annual Review of Biochemistry 61: 55–85.

27. BorowiecJA, DeanFB, BullockPA, HurwitzJ (1990) Binding and unwinding -how T antigen engages the SV40 origin of DNA replication. Cell 60: 181–184.

28. ZieglerK, BuiT, FrisqueRJ, GrandinettiA, NerurkarVR (2004) A rapid in vitro polyomavirus DNA replication assay. Journal of Virological Methods 122: 123–127.

29. NesperJ, SmithRWP, KautzAR, SockE, WegnerM, et al. (1997) A Cell-Free Replication System for Human Polyomavirus JC DNA. J of Virology 71: 7421–7428.

30. SimmonsDT (2000) SV40 Large T Antigen Functions in DNA Replication and Transformation. Advances in Virus Research 55: 75–134.

31. WagaS, StillmanB (1994) Anatomy of a DNA replication fork revealed by reconstitution of SV40 DNA replication in vitro. Nature (London) 369: 207–212.

32. HurwitzJ, DeanFB, KwongAD, LeeS-H (1990) The in vitro replication of DNA containing the SV40 origin. Journal of Biological Chemistry 265: 18043–18046.

33. KellyTJ (1988) SV40 DNA replication. J Biol Chem 263: 17889–17892.

34. Waga S, Stillman B (1998) The DNA Replication Fork in Eukaryotic Cells. In: Richardson CC, editor. Annual Review of Biochemistry. Palo Alto: Annual Reviews Inc. pp. 721–751.

35. TopalisD, AndreiG, SnoeckR (2013) The large tumor antigen: A “Swiss Army knife” protein possessing the functions required for the polyomavirus life cycle. Antiviral Research 97: 122–136.

36. FanningE, ZhaoK (2009) SV40 DNA replication: From the A gene to a nanomachine. Virology 384: 352–359.

37. Meinke G, Bullock PA (2012) Structural “snap-shots” of the initiation of SV40 replication. In: Gaston K, editor. Small DNA Tumor Viruses. Norwich: Horizon Scientific Press. pp. 195–215.

38. BullockPA (1997) The Initiation of Simian Virus 40 DNA Repliation in Vitro. Critical Reviews in Biochemistry and Molecular Biology 32: 503–568.

39. Wun-KimK, UpsonR, YoungW, MelendyT, StillmanB, et al. (1993) The DNA-binding domain of simian virus 40 tumor antigen has multiple functions. Journal of Virology 67: 7608–7611.

40. SimmonsDT, LoeberG, TegtmeyerP (1990) Four major sequence elements of simian virus 40 large T antigen coordinate its specific and nonspecific DNA binding. Journal of Virology 64: 1973–1983.

41. WeisshartK, TanejaP, JenneA, HerbigU, SimmonsDT, et al. (1999) Two Regions of Simian Virus 40 T Antigen Determine Cooperativity of Double-Hexamer Assembly on the Viral Origin of DNA Replication and Promote Hexamer Interactions during Bidirectional Origin DNA Unwinding. J of Virology 73: 2201–2211.

42. MeinkeG, PhelanPJ, MoineS, BochkarevaE, BochkarevA, et al. (2007) The crystal structure of the SV40 T-antigen origin binding domain in complex with DNA. PloS Biology 5: e23.

43. FosterEC, SimmonsDT (2010) The SV40 Large T-Antigen Origin Binding Domain Directly Participates in DNA Unwinding. Biochemistry 49: 2087–2096.

44. ReeseDK, MeinkeG, KumarA, MoineS, ChenK, et al. (2006) Analyses of the Interaction between the Origin Binding Domain from Simian Virus 40 T-antigen and single stranded DNA Provides Insights into DNA unwinding and Initiation of DNA Replication. Journal of Virology 80: 12248–12259.

45. MeinkeG, PhelanPJ, Fradet-TurcotteA, BohmA, ArchambaultJ, et al. (2011) Structure-Based Analysis of the Interaction between the SV40 T-Antigen Origin Binding Domain and ssDNA. Journal of Virology 85: 818–827.

46. JiangX, KlimovichV, ArunkumarAI, HysingerEB, WangY, et al. (2006) Structural mechanism of RPA loading on DNA during activation of a simple pre-replication complex. The EMBO Journal 25: 5516–5526.

47. ChangYP, XuM, MachadoACD, YuXJ, RohsR, et al. (2013) Mechanism of Origin DNA Recognition and Assembly of an Initiator-Helicase Complex by SV40 Large Tumor Antigen. Cell 3: 1–11.

48. LuoX, SanfordDG, BullockPA, BachovchinWW (1996) Structure of the origin specific DNA binding domain from simian virus 40 T-antigen. Nature Structural Biology 3: 1034–1039.

49. BochkarevaE, MartynowskiD, SeitovaA, BochkarevA (2006) Structure of the origin-binding domain of simian virus 40 large T antigen bound to DNA. The EMBO Journal 25: 5961–5969.

50. GaiD, ZhaoR, LiD, FinkielsteinCV, ChenXS (2004) Mechanisms of Conformational Change for a Replicative Hexameric Helicase of SV40 Large Tumor Antigen. Cell 119: 47–60.

51. LiD, ZhaoR, LilyestromW, GaiD, ZhangR, et al. (2003) Structure of the replicative helicase of the oncoprotein SV40 large tumour antigen. Nature 423: 512–518.

52. KimH-Y, AhnBY, ChoY (2001) Structural basis for the inactivation of retinoblastoma tumor suppressor by SV40 large T antigen. EMBOJ 20: 295–304.

53. ScalfaniRA, FletcherRJ, ChenXS (2004) Two heads are better than one: regulation of DNA replication by hexameric helicases. Genes and Development 18: 2039–2045.

54. FrisqueRJ, BreamGL, CannellaMT (1984) Human polyomavirus JC virus genome. Journal of Virology 51: 458–469.

55. LiJJ, KellyTJ (1985) Simian Virus 40 DNA Replication In Vitro: Specificity of Initiation and Evidence for Bidirectional Replication. Mol Cell Biol 5: 1238–1246.

56. FeigenbaumL, KhaliliK, MajorE, KhouryG (1987) Regulation of the host range of human papovavirus JCV. Proc Natl Acad Sci USA 84: 3695–3698.

57. MajorEO, MillerAE, MourrainP, TraubRG, de WidtE, et al. (1985) Establishment of a line of human fetal glial cells that supports JC virus multiplication. Proc NatlAcadSciUSA 82: 1257–1261.

58. CampbellKS, MullaneKP, AksoyIA, StubdalH, PipasJM, et al. (1997) DnaJ/hsp40 chaperone domain of SV40 large T antigen promotes efficient viral DNA replication. Genes & Dev 11: 1098–1110.

59. Otwinowski Z, Minor W (1997) Processing of X-ray Diffraction Data Collected in Oscillation Mode. In: Carter CW, Sweet RM, editors. Methods in Enzymology. New York: Academic Press. pp. 307–326.

60. McCoyAJ, Grosse-KunstleveRW, AdamsPD, WinnnMD, StoroniLC, et al. (2007) Phaser crystalographic software. Jounal of applied crystallography 40: 658–674.

61. WinnMD, BallardCC, CowtanKD, DodsonEJ, EmsleyP, et al. (2011) Overview of the CCP4 suite and current developments. Acta crystallographica Section D, Biological crystallography 67: 235–242.

62. BramucchiE, PaiardiniA, BossaF, PascarellaS (2012) PyMod: sequence similarity searches, multiple sequence-structural alignments, and homology modeling within PyMOL. BMC Bioinformatics 13: S2.

63. MeinkeG, BullockPA, BohmA (2006) The crystal structure of the T-ag origin binding domain. J of Virology 80: 4304–4312.

64. LangerG, CohenSX, LamzinVS, PerrakisA (2008) Automated macromolecular model building for X-ray crystallography using ARP/wARP version 7. Nature Protocols 3: 1171–1179.

65. MurshudovGN, SkubakP, LebedevAA, PannuNS, SteinerRA, et al. (2011) REFMAC5 for the refinement of macromolecular crystal structures. Acta crystallographica Section D, Biological crystallography 67: 355–367.

66. AdamsPD, AfoninePV, BunkocziG, ChenVB, DavisIW, et al. (2010) PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr 66: 213–221.

67. EmsleyP, LohkampB, ScottWG, CowtanK (2010) Features and development of Coot. Acta Crystallogr D Biol Crystallogr 66: 486–501.

68. LebedevA, YoungP, IsupovMN, MorozOV, VaginAA, et al. (2012) JLigand: a graphical tool for the CCP4 template-restraint library. Acta Cryst D68: 431–440.

69. KrissinelE, HenrickK (2004) Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions. Acta Crystallogr D Biol Crystallogr 60: 2256–2268.

70. LaskowskiRA (2009) PDBsum new things. Nucleic Acids Res 37: D355–359.

71. KrissinelE, HenrickK (2007) Inference of macromolecular assemblies from crystalline state. J of Mol Biol 372: 774–797.

72. DeLano WL (2002) The PyMOL Molecular Graphics System. Delano Scientific, Palo Alto, CA USA.

73. SieversF, WilmA, DineenD, GibsonTJ, KarplusK, et al. (2011) Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Molecular systems biology 7: 539.

74. WaterhouseAM, ProcterJB, MartinDM, ClampM, BartonGJ (2009) Jalview Version 2–a multiple sequence alignment editor and analysis workbench. Bioinformatics 25: 1189–1191.

75. Fradet-TurcotteA, MorinG, LehouxM, BullockPA, ArchambaultJ (2010) Development of quantitative and high-throughput assays of polyomavirus and papillomavirus DNA replication. Virology 399: 65–76.

76. MeinkeG, PhelanPJ, HarrisonCJ, BullockPA (2013) Analysis of the costructure of the simian virus 40 T-antigen origin binding domain with site I reveals a correlation between GAGGC spacing and spiral assembly. Journal of Virology 87: 2923–2934.

77. MeinkeG, PhelanP, Fradet-TurcotteA, ArchambaultJ, BullockPA (2011) Structure-based design of a disulfide-linked oligomeric form of the Simian Virus 40 (SV40) large T antigen DNA-binding domain. Acta Crystallogr D Biol Crystallogr D67: 560–567.

78. ChukeWF, WalkerDL, PeitzmanLB, FrisqueRJ (1986) Construction and characterization of hybrid polyomavirus genomes. Journal of Virology 60: 960–971.

79. HarrisonCJ, MeinkeG, KwunHJ, RogalinH, PhelanPJ, et al. (2011) Asymmetric Assembly of Merkel Cell Polyomavirus Large T-antigen Origin Binding Domain at the Viral Origin. Journal of Molecular Biology 409: 529–542.

80. TegtmeyerP, SchwartzM, CollinsJK, RundellK (1975) Regulation of tumor antigen synthesis by simian virus 40 gene A. J Virology 16: 168–178.

81. AlwineJC, ReedSI, StarkGR (1977) Characterization of the autoregulation of simian virus 40 gene A. J Virology 24: 22–27.

82. KhouryG, MayE (1977) Regulation of early and late simian virus 40 transcription: Overproduction of early viral RNA in the absence of a functional T-antigen. J Virology 23: 167–176.

83. GuoZS, HeineU, DePamphilisML (1991) T-antigen binding to site I facilitates initiation of SV40 DNA replication but does not affect bidirectionality. Nucleic Acids Res 19: 7081–7088.

84. KumarA, MeinkeG, ReeseDK, MoineS, PhelanPJ, et al. (2007) Model for T-antigen-dependent melting of the simian virus 40 core origin based on studies of the interaction of the beta-hairpin with DNA. J Virol 81: 4808–4818.

85. CuestaI, Nunez-RamirezR, ScheresSHW, GaiD, ChenXS, et al. (2010) Conformational Rearrangements of SV40 Large T Antigen during Early Replication Events. J Mol Biol 397: 1276–1286.

86. ValleM, GrussC, HalmerL, CarazoJM, DonateLE (2000) Large T-Antigen Double Hexamers Imaged at the Simian Virus 40 Origin of Replication. Mol Cell Biol 20: 34–41.

87. MastrangeloIA, HoughPVC, WallJS, DodsonM, DeanFB, et al. (1989) ATP-dependent assembly of double hexamers of SV40 T antigen at the viral origin of DNA replication. Nature (London) 338: 658–662.

88. VanLoockMS, AlexandrovA, YuX, CozzarelliNR, EgelmanEH (2002) SV40 Large T Antigen Hexamer Structure: Domain Organization and DNA-Induced Conformational Changes. Current Biology 12: 472–476.

89. BollagB, MackeenPC, FrisqueRJ (1996) Purified JC Virus T Antigen Derived from Insect Cells Preferentially Interacts with Binding Site II of the Viral Core Origin under Replication Conditions. Virology 218: 81–93.

90. ClareyMG, ErzbergerJP, GrobP, LeschzinerAE, BergerJM, et al. (2006) Nucleotide-dependent conformational changes in the DnaA-like core of the origin recognition complex. nature Struct MolBiol 13: 684–690.

91. LyubimovAY, CostaA, BleichertF, BotchanMR, BergerJM (2012) ATP-dependent conformational dynamics underlie the functional asymmetry of the replicative helicase form a minimalist eukaryote. Proc NatlAcadSciUSA 109: 11999–12004.

92. ErzbergerJP, MottML, BergerJM (2006) Structural basis for ATP-dependent DNA assembly and replication-origin remodeling. Nature Structural & Molecular Biology 13: 676–683.

93. ItsathitphaisarnO, WingRA, EliasonWK, JW, SteitzTA (2012) The hexameric helicase DnaB Adopts a Nonplanar Conformation during Translocation. Cell 1512: 267–277.

94. O'DonnellM, JeruzalmiD (2006) Helical proteins initiate replication of DNA helices. nature Struct MolBiol 13: 665–667.

95. Fradet-TurcotteA, VincentC, JoubertS, BullockPA, ArchambaultJ (2007) Quantitative Analysis of the Binding of Simian Virus 40 large T Antigen to DNA. Journal of Virology 81: 9162–9174.

96. JooWS, KimHY, PurvianceJD, SreekumarKR, BullockPA (1998) Assembly of T-antigen Double Hexamers on the Simian Virus 40 Core Origin Requires Only a Subset of the Available Binding Sites. Mol Cell Biol 18: 2677–2687.

97. SreekumarKR, PrackAE, WintersDR, BarbaroBA, BullockPA (2000) The Simian Virus 40 Core Origin Contains Two Separate Sequence Modules That Support T-Antigen Double-Hexamer Assembly. J of Virology 74: 8589–8600.

98. HarrisonC, JiangT, BanerjeeP, MeinkeG, D'AbramoCM, et al. (2013) Polyomavirus Large T-antigen Binds Symmetrical Repeats at the Viral Origin in an Asymmetrical Manner. Journal of Virology 87: 13751–13759.

99. WuX, AvniD, ChibaT, YanF, ZhaoQ, et al. (2004) SV40 T antigen interacts with Nbs1 to disrupt DNA replication control. Genes and Development 18: 1305–1316.

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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