Journal of Molecular Modeling

, Volume 12, Issue 6, pp 921–929 | Cite as

Determining functionally important amino acid residues of the E1 protein of Venezuelan equine encephalitis virus

  • Surendra S. Negi
  • Andrey A. Kolokoltsov
  • Catherine H. Schein
  • Robert A. Davey
  • Werner Braun
Original paper

Abstract

A new method for predicting interacting residues in protein complexes, InterProSurf, was applied to the E1 envelope protein of Venezuelan equine encephalitis (VEEV). Monomeric and trimeric models of VEEV-E1 were constructed with our MPACK program, using the crystal structure of the E1 protein of Semliki forest virus as a template. An alignment of the E1 sequences from representative alphavirus sequences was used to determine physical chemical property motifs (likely functional areas) with our PCPMer program. Information on residue variability, propensity to be in protein interfaces, and surface exposure on the model was combined to predict surface clusters likely to interact with other viral or cellular proteins. Mutagenesis of these clusters indicated that the predictions accurately detected areas crucial for virus infection. In addition to the fusion peptide area in domain 2, at least two other surface areas play an important role in virus infection. We propose that these may be sites of interaction between the E1–E1 and E1–E2 subdomains of the envelope proteins that are required to assemble the functional unit. The InterProSurf method is, thus, an important new tool for predicting viral protein interactions. These results can aid in the design of new vaccines against alphaviruses and other viruses.

D model of the E1 protein of VEEV showing a comparison of interface residues (green) predicted by InterProSurf (left view) and residues showing the experimental effect of mutations on the titer of pseudotyped MLV particles with red most dramatic changes and blue as wild type

Keywords

Venezuelan equine encephalitis virus (VEEV) Alpha virus Protein–protein interaction Envelope glycoprotein Functional site prediction 

References

  1. 1.
    Wenger F (1977) Teratology 16:359–362CrossRefPubMedGoogle Scholar
  2. 2.
    Paessler S, Fayzulin RZ, Anishchenko M, Greene IP, Weaver SC, Frolov I (2003) J Virol 77:9278–9286CrossRefPubMedGoogle Scholar
  3. 3.
    Weaver SC, Ferro C, Barrera R, Boshell J, Navarro JC (2004) Annu Rev Entomol 49:141–174CrossRefPubMedGoogle Scholar
  4. 4.
    Kinney RM, Tsuchiya KR, Sneider JM, Trent DW (1992) Virology 191:569–580CrossRefPubMedGoogle Scholar
  5. 5.
    Zhang W, Mukhopadhyay S, Pletnev SV, Baker TS, Kuhn RJ, Rossmann MG (2002) J Virol 76:11645–11658CrossRefPubMedGoogle Scholar
  6. 6.
    Zhang W, Fisher BR, Olson NH, Strauss JH, Kuhn RJ, Baker TS (2002) J Virol 76:7239–7246CrossRefPubMedGoogle Scholar
  7. 7.
    Lescar J, Roussel A, Wien MW, Navaza J, Fuller SD, Wengler G, Rey FA (2001) Cell 105:137–148CrossRefPubMedGoogle Scholar
  8. 8.
    Paredes A, Alwell-Warda K, Weaver SC, Chiu W, Watowich SJ (2003) J Virol 77:659–664CrossRefPubMedGoogle Scholar
  9. 9.
    Gibbons DL, Vaney MC, Roussel A, Vigouroux A, Reilly B, Lepault J, Kielian M, Rey FA (2004) Nature 427:320–325CrossRefPubMedGoogle Scholar
  10. 10.
    Kolokoltsov AA, Davey RA (2004) J Virol 78:5124–5132CrossRefPubMedGoogle Scholar
  11. 11.
    Soman KV, Midoro-Horiuti T, Ferreon JC, Goldblum RM, Brooks EG, Kurosky A, Braun W, Schein CH (2000) Biophys J 79:1601–1609PubMedGoogle Scholar
  12. 12.
    Schein CH, Nagle GT, Page JS, Sweedler JV, Xu Y, Painter SD, Braun W (2001) Biophys J 81:463–472PubMedGoogle Scholar
  13. 13.
    Soman KV, Schein CH, Zhu H, Braun W (2001) Methods Mol Biol 160:263–286PubMedGoogle Scholar
  14. 14.
    Ivanciuc O, Oezguen N, Mathura VS, Schein CH, Xu Y, Braun W (2004) Curr Med Chem 11:583–593CrossRefPubMedGoogle Scholar
  15. 15.
    Schein CH, Zhou B, Oezguen N, Mathura VS, Braun W (2005) Proteins: Struct, Funct, Bioinf 58:200–210CrossRefGoogle Scholar
  16. 16.
    Schaumann T, Braun W, Wuthrich K (1990) Biopolymers 29:679–694CrossRefGoogle Scholar
  17. 17.
    Laskowski RA, Macarthur MW, Moss DS, Thornton JM (1993) J Appl Crystallogr 26:283–291CrossRefGoogle Scholar
  18. 18.
    Koradi R, Billeter M, Wuthrich K (1996) J Mol Graph 14:51–55CrossRefGoogle Scholar
  19. 19.
    Mancini EJ, Clarke M, Gowen BE, Rutten T, Fuller SD (2000) Mol Cell 5:255–266CrossRefPubMedGoogle Scholar
  20. 20.
    Ginalski K, Elofsson A, Fischer D, Rychlewski L (2003) Bioinformatics 19:1015–1018CrossRefPubMedGoogle Scholar
  21. 21.
    Cuff JA, Clamp ME, Siddiqui AS, Finlay M, Barton GJ (1998) Bioinformatics 14:892–893CrossRefPubMedGoogle Scholar
  22. 22.
    Linde Y, Buzo A, Gray RM (1980) IEEE Trans Commun 28:84–95CrossRefGoogle Scholar
  23. 23.
    Sayood K (2000) Introduction to data compression, 2nd edn. Kaufmann, San Francisco, CAGoogle Scholar
  24. 24.
    Singh RK, Tropsha A, Vaisman II (1996) J Comput Biol 3:213–221PubMedCrossRefGoogle Scholar
  25. 25.
    Liang J, Edelsbrunner H, Woodward C (1998) Protein Sci 7:1884–1897PubMedCrossRefGoogle Scholar
  26. 26.
    Landgraf R, Xenarios I, Eisenberg D (2001) J Mol Biol 307:1487–1502CrossRefPubMedGoogle Scholar
  27. 27.
    De-Alarcon PA, Pascual-Montano A, Gupta A, Carazo JM (2002) Biophys J 83:619–632PubMedGoogle Scholar
  28. 28.
    Patane G, Russo M (2001) Neural Netw 14:1219–1237CrossRefPubMedGoogle Scholar
  29. 29.
    Fraczkiewicz R, Braun W (1998) J Comput Chem 19:319–333CrossRefGoogle Scholar
  30. 30.
    Schein CH, Zhou B, Braun W (2005) Virol J 2:40CrossRefPubMedGoogle Scholar
  31. 31.
    Mathura VS, Schein CH, Braun W (2003) Bioinformatics 19:1381–1390CrossRefPubMedGoogle Scholar
  32. 32.
    Bressanelli S, Stiasny K, Allison SL, Stura EA, Duquerroy S, Lescar J, Heinz FX, Rey FA (2004) EMBO J 23:728–738CrossRefPubMedGoogle Scholar
  33. 33.
    Sigrist CJ, Cerutti L, Hulo N, Gattiker A, Falquet L, Pagni M, Bairoch APB (2002) Brief Bioinform 3:265–274PubMedCrossRefGoogle Scholar
  34. 34.
    Pletnev SV, Zhang W, Mukhopadhyay S, Fisher BR, Hernandez R, Brown DT, Baker TS, Rossmann MG, Kuhn RJ (2001) Cell 105:127–136CrossRefPubMedGoogle Scholar
  35. 35.
    DeLano WL (2002) Curr Opin Struct Biol 12:14–20CrossRefPubMedGoogle Scholar
  36. 36.
    Bogan AA, Thorn KS (1998) J Mol Biol 280:1–9CrossRefPubMedGoogle Scholar
  37. 37.
    Shome SG, Kielian M (2001) Virology 279:146–160CrossRefPubMedGoogle Scholar
  38. 38.
    Han X, Bushweller JH, Cafiso DS, Tamm LK (2001) Nat Struct Biol 8:715–720CrossRefPubMedGoogle Scholar
  39. 39.
    Tamm LK, Han X, Li YL, Lai AL (2002) Biopolymers 66:249–260CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Surendra S. Negi
    • 1
  • Andrey A. Kolokoltsov
    • 2
  • Catherine H. Schein
    • 1
  • Robert A. Davey
    • 2
  • Werner Braun
    • 1
    • 3
  1. 1.Sealy Center for Structural Biology, Department of Biochemistry and Molecular BiologyUniversity of Texas Medical BranchGalvestonUSA
  2. 2.Department of Microbiology and ImmunologyUniversity of Texas Medical BranchGalvestonUSA
  3. 3.University of Texas Medical BranchGalvestonUSA

Personalised recommendations