Este artículo es de Acceso Abierto y puede ser descargado en su versión final desde nuestro repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


Papillomaviruses are small DNA tumor viruses that infect mammalian hosts, with consequences from benign to cancerous lesions. The Early protein 2 is the master regulator for the virus life cycle, participating in gene transcription, DNA replication, and viral episome migration. All of these functions rely on primary target recognition by its dimeric DNA-binding domain. In this work, we performed molecular dynamics simulations in order to gain insights into the structural dynamics of the DNA-binding domains of two prototypic strains, human papillomavirus strain 16 and the bovine papillomavirus strain 1. The simulations underline different dynamic features in the two proteins. The human papillomavirus strain 16 domain displays a higher flexibility of the β2-β3 connecting loop in comparison with the bovine papillomavirus strain 1 domain, with a consequent effect on the DNA-binding helices, and thus on the modulation of DNA recognition. A compact β-barrel is found in human papillomavirus strain 16, whereas the bovine papillomavirus strain 1 protein is characterized by a loose β-barrel with a large number of cavities filled by water, which provides great flexibility. The rigidity of the human papillomavirus strain 16 β-barrel prevents protein deformation, and, as a consequence, deformable spacers are the preferred targets in complex formation. In contrast, in bovine papillomavirus strain 1, a more deformable β-barrel confers greater adaptability to the protein, allowing the binding of less flexible DNA regions. The flexibility data are confirmed by the experimental NMR S2 values, which are reproduced well by calculation. This feature may provide the protein with an ability to discriminate between spacer sequences. Clearly, the deformability required for the formation of the Early protein 2 C-terminal DNA-binding domain-DNA complexes of various types is based not only on the rigidity of the base sequences in the DNA spacers, but also on the intrinsic deformability properties of each domain. © 2007 The Authors.


Documento: Artículo
Título:Molecular dynamics of the DNA-binding domain of the papillomavirus E2 transcriptional regulator uncover differential properties for DNA target accommodation
Autor:Falconi, M.; Santolamazza, A.; Eliseo, T.; De Prat-Gay, G.; Cicero, D.O.; Desideri, A.
Filiación:Department of Biology, CIBB (Centro Interdipartimentale di Biostatistica e Bioinformatica), University of Rome 'Tor Vergata', Italy
Department of Science and Chemical Technologies, University of Rome 'Tor Vergata', Italy
Instituto de Investigaciones Bioquimicas Fundación Leloir, Facultad de Ciencias Exactas Y Naturales and CONICET, Universidad de Buenos Aires, Argentina
Department of Biology, University of Rome 'Tor Vergata', Via della Ricerca Scientifica, 00133 Rome, Italy
Palabras clave:Molecular dynamics simulation; Papillomavirus; Protein flexibility; Protein-DNA recognition; Transcription factor; early protein 2; transcription factor; unclassified drug; amino acid sequence; article; carboxy terminal sequence; controlled study; DNA binding; gene targeting; Human papillomavirus type 16; molecular dynamics; molecular recognition; nonhuman; nuclear magnetic resonance spectroscopy; Papilloma virus; priority journal; protein DNA binding; protein domain; protein structure; simulation; transcription regulation; virus strain; Animals; Bovine papillomavirus 1; Cattle; DNA, Viral; DNA-Binding Proteins; Human papillomavirus 16; Humans; Oncogene Proteins, Viral; Principal Component Analysis; Protein Binding; Protein Conformation; Protein Structure, Secondary; Viral Proteins; Bovine papillomavirus; Human papillomavirus; Mammalia; Papillomaviridae
Página de inicio:2385
Página de fin:2395
Título revista:FEBS Journal
Título revista abreviado:FEBS J.
CAS:DNA, Viral; DNA-Binding Proteins; E2 protein, Bovine papillomavirus; E2 protein, Human papillomavirus type 16; Oncogene Proteins, Viral; Viral Proteins


  • Hegde, R.S., The papillomavirus E2 proteins: Structure, function, and biology (2002) Annu Rev Biophys Biomol Struct, 31, pp. 343-360
  • Androphy, E.J., Lowy, D.R., Schiller, J.T., Bovine papillomavirus E2 trans-acting gene product binds to specific sites in papillomavirus DNA (1987) Nature, 325, pp. 70-73
  • Romanczuk, H., Thierry, F., Howley, P.M., Mutational analysis of cis-elements involved in E2 modulation of human papillomavirus type 16 P97 and type 18 P105 promoters (1990) J Virol, 64, pp. 2849-2859
  • Chiang, C.M., Ustav, M., Stenlund, A., Ho, T.F., Broker, T.R., Chow, L.T., Viral E1 and E2 proteins support replication of homologous and heterologous papillomavirus origins (1992) Proc Natl Acad Sci USA, 89, pp. 5799-5803
  • Del Vecchio, A.M., Romaczuk, H., Howley, P.M., Baker, C.C., Transient replication of human papillomavirus DNAs (1992) J Virol, 66, pp. 5949-5958
  • Ustav, M., Stenlund, A., Transient replication of BPV-1 requires two viral polypeptides encoded by the E1 and E2 open reading frames (1991) EMBO J, 10, pp. 449-457
  • Giri, I., Yaniv, M., Structural and mutational analysis of E2 trans-activating proteins of papillomaviruses reveals three distinct functional domains (1988) EMBO J, 7, pp. 2823-2829
  • Veeraraghavan, S., Mello, C., Androphy, E., Baleja, J.D., Structural correlates for enhanced stability in the E2 DNA-binding domain from bovine papillomavirus (1999) Biochemistry, 38, pp. 16115-16124
  • Hegde, R.S., Wang, A.F., Kim, S.S., Schapira, M., Subunit rearrangement accompanies sequence-specific DNA-binding by the bovine papillomavirus-1 E2 protein (1998) J Mol Biol, 276, pp. 797-808
  • Hegde, R.S., Grossman, S.R., Laimins, L.A., Sigler, P.B., Crystal structure at 1.7 Å of the bovine papillomavirus-1 E2 DNA-binding domain bound to its DNA target (1992) Nature, 359, pp. 505-512
  • Hegde, R.S., Androphy, E.J., Crystal structure of the E2 DNA-binding domain from human papillomavirus type 16: Implications for its DNA binding-site selection mechanism (1998) J Mol Biol, 284, pp. 1479-1489
  • Nadra, A.D., Eliseo, T., Mok, Y.K., Almeida, C.L., Bycroft, M., Paci, M., De Prat-Gay, G., Cicero, D.O., Solution structure of the HPV-16 E2 DNA binding domain, a transcriptional regulator with a dimeric beta-barrel fold (2004) J Biomol NMR, 30, pp. 211-214
  • Cicero, D.O., Nadra, A.D., Eliseo, T., Dellarole, M., Paci, M., De Prat-Gay, G., Structural and thermodynamic basis for the enhanced transcriptional control by the human papillomavirus strain-16 E2 protein (2006) Biochemistry, 45, pp. 6551-6560
  • Bochkarev, A., Barwell, J.A., Pfuetzner, R.A., Furey Jr., W., Edwards, A.M., Frappier, L., Crystal structure of the DNA-binding domain of the Epstein-Barr virus origin-binding protein EBNA 1 (1995) Cell, 83, pp. 39-46
  • De Prat-Gay, G., Nadra, A.D., Corrales-Izquierdo, F.J., Alonso, L.G., Ferreiro, D.U., Mok, Y.K., The folding mechanism of a dimeric beta-barrel domain (2005) J Mol Biol, 351, pp. 672-682
  • Bedrosian, C.L., Bastia, D., The DNA-binding domain of HPV-16 E2 protein interaction with the viral enhancer: Protein-induced DNA bending and role of the non-conserved core sequence in binding site affinity (1990) Virology, 174, pp. 557-575
  • Hines, C.S., Meghoo, C., Shetty, S., Biburger, M., Brenowitz, M., Hegde, R.S., DNA structure and flexibility in the sequence-specific binding of papillomavirus E2 proteins (1998) J Mol Biol, 276, pp. 809-818
  • Hizver, J., Rozenberg, H., Frolow, F., Rabinovich, D., Shakked, Z., DNA bending by an adenine-thymine tract and its role in gene regulation (2001) Proc Natl Acad Sci USA, 98, pp. 8490-8495
  • Djuranovic, D., Oguey, C., Hartmann, B., The role of DNA structure and dynamics in the recognition of bovine papillomavirus E2 protein target sequences (2004) J Mol Biol, 339, pp. 785-796
  • Djuranovic, D., Hartmann, B., Molecular dynamics studies on free and bound targets of the bovine papillomavirus type I e2 protein: The protein binding effect on DNA and the recognition mechanism (2005) Biophys J, 89, pp. 2542-2551
  • Pepinsky, R.B., Prakash, S.S., Corina, K., Grossel, M.J., Barsoum, J., Androphy, E.J., Sequences flanking the core DNA-binding domain of bovine papillomavirus type 1 E2 contribute to DNA-binding function (1997) J Virol, 71, pp. 828-831
  • Ferreiro, D., Dellarole, M., Nadra, A.D., De Prat-Gay, G., Free energy contributions to direct readout of a DNA sequence (2005) J Biol Chem, 280, pp. 32480-32484
  • Lipari, G., Szabo, A., Model-free approach to the interpretation of nuclear magnetic resonance relaxation in macromolecules. 1. Theory and range of validity (1982) J Am Chem Soc, 104, pp. 4546-4559
  • Henry, E.R., Szabo, A., Influence of vibrational motion on solid state line shapes and NMR relaxation (1985) J Chem Phys, 82, pp. 4753-4761
  • Hu, H., Clarkson, M.W., Hermans, J., Lee, A.L., Increased rigidity of eglin c at acidic pH: Evidence from NMR spin relaxation and MD simulations (2003) Biochemistry, 42, pp. 13856-13868
  • Laskowski, R.A., SURFNET: A program for visualizing molecular surfaces, cavities, and intermolecular interactions (1995) J Mol Graph, 13, pp. 323-330
  • Garcia, A.E., Large-amplitude nonlinear motions in proteins (1992) Phys Rev Lett, 68, pp. 2696-2699
  • Amadei, A., Linssen, A.B., Berendsen, H.J., Essential dynamics of proteins (1993) Proteins, 17, pp. 412-425
  • Liang, H., Petros, A.M., Meadows, R.P., Yoon, H.S., Egan, D.A., Walter, K., Holzman, T.F., Fesik, S.W., (1996) Biochemistry, 35, pp. 2095-2103
  • Gromiha, M.M., Siebers, J.G., Selvaraj, S., Kono, H., Sarai, A., Intermolecular and intramolecular readout mechanisms in protein-DNA recognition (2004) J Mol Biol, 337, pp. 285-294
  • Case, D.A., Cheatham Iii., T.E., Darden, T., Gohlke, H., Luo, R., Merz, K.M., Onufriev Jr., A., Woods, R., The Amber biomolecular simulation programs (2005) J Comput Chem, 26, pp. 1668-1688
  • Cornell, W.D., Cieplak, P., Bayly, C.I., Gould, I.R., Kenneth, M., Merz, J., Ferguson, D.M., Caldwell, J.W., A second generation force field for the simulations of proteins, nucleic acids and organic molecules (1995) J Am Chem Soc, 117, pp. 5179-5197
  • Ponder, J.W., Case, D.A., Force fields for protein simulations (2003) Adv Prot Chem, 66, pp. 27-85
  • Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R.W., Klein, M.L., Comparison of simple potential functions for simulating liquid water (1983) J Chem Phys, 79, pp. 926-935
  • Berendsen, H.J.C., Postma, J.P.M., Van Gusteren, W.F., Di Nola, A., Haak, J.R., Molecular dynamics with coupling to an external bath (1984) J Comput Phys, 81, pp. 3684-3690
  • Darden, T., York, D., Pedersen, L., Particle mesh Ewald and N.log (n) method for Ewald sums in large systems (1993) J Chem Phys, 98, pp. 10089-10092
  • Cheatham, T.E., Miller, J.L., Fox, T., Darden, T.A., Kolman, P.A., Molecular dynamics simulation on solvated biomolecular systems: The particle mesh Ewald method leads to stable trajectories of DNA, RNA and proteins (1995) J Am Chem Soc, 117, pp. 4193-4194
  • Ryckaert, J.P., Ciccotti, G., Berendsen, H.J.C., Numerical integration of the Cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes (1977) J Comput Phys, 23, pp. 327-341
  • Berendsen, H.J.C., Van Der Spool, D., Van Drunen, R., GROMACS: A message-passing parallel molecular dynamics implementation (1995) Comp Phys Commun, 95, pp. 43-56
  • Kabsch, W., Sander, C., Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features (1983) Biopolymers, 22, pp. 2577-2637
  • Kay, L.E., Torchia, D.A., Bax, A., Backbone dynamics of proteins as studied by 15N inverse detected heteronuclear NMR spectroscopy: Application to staphylococcal nuclease (1989) Biochemistry, 28, pp. 8972-8979
  • Barbato, G., Ikura, M., Kay, L.E., Pastor, R.W., Bax, A., Backbone dynamics of calmodulin studied by 15N relaxation using inverse detected two-dimensional NMR spectroscopy: The central helix is flexible (1992) Biochemistry, 31, pp. 5269-5278
  • Orekhov, V.Y., Nolde, D.E., Golovanov, A.P., Korzhnev, P.M., Arseniev, A.S., Processing of heteronuclear NMR relaxation data with the new software DASHA (1995) Appl Magn Reson, 9, pp. 581-588
  • Stone, M.J., Fairbrother, W.J., Palmer, A.G., Reizer, J., Saier, M.H., Wright, P.E., Backbone dynamics of the Bacillus subtilis glucose permease IIA domain determined from 15N NMR relaxation measurements (1992) Biochemistry, 31, pp. 4394-4406
  • Kraulis, P.J., MOLSCRIPT: A program to produce both detailed and schematic plots of protein structures (1991) J Appl Crystallogr, 24, pp. 946-950
  • Sayle, R.A., Milner-White, E.J., RasMol: Biomolecular graphics for all (1995) Trends Biochem Sci, 20, pp. 374-376
  • Humphrey, W., Dalke, A., Schulten, K., VMD - Visual Molecular Dynamics (1996) J Mol Graph, 14, pp. 33-38


---------- APA ----------
Falconi, M., Santolamazza, A., Eliseo, T., De Prat-Gay, G., Cicero, D.O. & Desideri, A. (2007) . Molecular dynamics of the DNA-binding domain of the papillomavirus E2 transcriptional regulator uncover differential properties for DNA target accommodation. FEBS Journal, 274(9), 2385-2395.
---------- CHICAGO ----------
Falconi, M., Santolamazza, A., Eliseo, T., De Prat-Gay, G., Cicero, D.O., Desideri, A. "Molecular dynamics of the DNA-binding domain of the papillomavirus E2 transcriptional regulator uncover differential properties for DNA target accommodation" . FEBS Journal 274, no. 9 (2007) : 2385-2395.
---------- MLA ----------
Falconi, M., Santolamazza, A., Eliseo, T., De Prat-Gay, G., Cicero, D.O., Desideri, A. "Molecular dynamics of the DNA-binding domain of the papillomavirus E2 transcriptional regulator uncover differential properties for DNA target accommodation" . FEBS Journal, vol. 274, no. 9, 2007, pp. 2385-2395.
---------- VANCOUVER ----------
Falconi, M., Santolamazza, A., Eliseo, T., De Prat-Gay, G., Cicero, D.O., Desideri, A. Molecular dynamics of the DNA-binding domain of the papillomavirus E2 transcriptional regulator uncover differential properties for DNA target accommodation. FEBS J. 2007;274(9):2385-2395.