Prediction of Transmembrane Topology and Signal Peptide Given a Protein’s Amino Acid Sequence

  • Lukas Käll
Part of the Methods in Molecular Biology book series (MIMB, volume 673)


Here, we describe transmembrane topology and signal peptide predictors and highlight their advantages and shortcomings. We also discuss the relation between these two types of prediction.

Key words

Membrane protein signal peptide transmembrane topology prediction bioinformatics 


  1. 1.
    Ehrmann, M., Boyd, D., and Beckwith, J. (1990) Genetic analysis of membrane protein topology by a sandwich gene fusion approach. Proceedings of the National Academy of Sciences of the United States of America 87, 7574–7578.PubMedCrossRefGoogle Scholar
  2. 2.
    Manoil, C. and Beckwith, J. (1986) A genetic approach to analyzing membrane protein topology, Science 233, 1403–1408.PubMedCrossRefGoogle Scholar
  3. 3.
    Feilmeier, B.J., Iseminger, G., Schroeder, D., Webber, H., and Phillips, G.J. (2000) Green fluorescent protein functions as a reporter for protein localization in Escherichia coli. Journal of Bacteriology 182, 4068–4076.PubMedCrossRefGoogle Scholar
  4. 4.
    Hart, G.W., Brew, K., Grant, G.A., Bradshaw, R.A., and Lennarz, W.J. (1979) Primary structural requirements for the enzymatic formation of the N-glycosidic bond in glycoproteins. Studies with natural and synthetic peptides. The Journal of Biological Chemistry 254, 9747–9753.PubMedGoogle Scholar
  5. 5.
    Wu, C.C., MacCoss, M.J., Howell, K.E., and Yates, J.R., III (2003) A method for the comprehensive proteomic analysis of membrane proteins. Nature Biotechnology 21, 532–538.PubMedCrossRefGoogle Scholar
  6. 6.
    Chen, C.P., Kernytsky, A., and Rost, B. (2002) Transmembrane helix predictions revisited. Protein Science 11, 2774–2791.PubMedCrossRefGoogle Scholar
  7. 7.
    Argos, P., Rao, J.K., and Hargrave, P.A. (1982) Structural prediction of membrane-bound proteins. European Journal of Bio­chemistry 128, 565–575.PubMedCrossRefGoogle Scholar
  8. 8.
    Kyte, J. and Doolittle, R.F. (1982) A simple method for displaying the hydropathic character of a protein. Journal of Molecular Biology 157, 105–132.PubMedCrossRefGoogle Scholar
  9. 9.
    von Heijne, G. (1986) The distribution of positively charged residues in bacterial inner membrane proteins correlates with the trans-membrane topology. EMBO Journal 5, 3021–3027.PubMedGoogle Scholar
  10. 10.
    von Heijne, G. (1992) Membrane protein structure prediction: hydrophobicity analysis and the positive-inside rule. Journal of Molecular Biology 225, 487–494.CrossRefGoogle Scholar
  11. 11.
    Mitaku, S., Hirokawa, T., and Tsuji, T. (2002) Amphiphilicity index of polar amino acids as an aid in the characterization of amino acid preference at membrane-water interfaces. Bioinformatics 18, 608–616.PubMedCrossRefGoogle Scholar
  12. 12.
    Rost, B., Casadio, R., Fariselli, P., and Sander, C. (1995) Transmembrane helices predicted at 95% accuracy. Protein Science 4, 521–533.PubMedCrossRefGoogle Scholar
  13. 13.
    Lo, A., Chiu, H.S., Sung, T.Y., Lyu, P.C., and Hsu, W.L. (2008) Enhanced membrane protein topology prediction using a hierarchical classification method and a new scoring function. Journal of Proteome Research 7, 487–496.PubMedCrossRefGoogle Scholar
  14. 14.
    Jones, D.T., Taylor, W.R., and Thornton, J.M. (1994) A model recognition approach to the prediction of all-helical membrane protein structure and topology. Biochemistry 33, 3038–3049.PubMedCrossRefGoogle Scholar
  15. 15.
    Dempster, A.P., Laird, N.M., and Rubin, D.B. (1977) Maximum likelihood from incomplete data via the EM algorithm. Journal of the Royal Statistical Society 39, 1–22.Google Scholar
  16. 16.
    Tusnady, G.E. and Simon, I. (1998) Principles governing amino acid composition of integral membrane proteins: application to topology prediction. Journal of Molecular Biology 283, 489–506.PubMedCrossRefGoogle Scholar
  17. 17.
    Tusnady, G.E. and Simon, I. (2001) The HMMTOP transmembrane topology prediction server. Bioinformatics 17, 849–850.PubMedCrossRefGoogle Scholar
  18. 18.
    Sonnhammer, E.L., von Heijne, G., and Krogh, A. (1998) A hidden Markov model for predicting transmembrane helices in protein sequences. Proceedings of the Sixth International Conference on Intelligent Systems for Molecular Biology 6, 175–182.Google Scholar
  19. 19.
    Krogh, A., Larsson, B., von Heijne, G., and Sonnhammer, E.L. (2001) Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. Journal of Molecular Biology 305, 567–580.PubMedCrossRefGoogle Scholar
  20. 20.
    Käll, L., Krogh, A., and Sonnhammer, E.L.L. (2004) A combined transmembrane topology and signal peptide prediction method. Journal of Molecular Biology 338, 1027–1036.PubMedCrossRefGoogle Scholar
  21. 21.
    Reynolds, S.M., Käll, L., Riffle, M.E., Bilmes, J.A., and Noble, W.S. (2008) Transmembrane topology and signal peptide prediction using dynamic bayesian networks. PLoS Computational Biology 4, e1000213.PubMedCrossRefGoogle Scholar
  22. 22.
    Hessa, T., Kim, H., Bihlmaier, K., Lundin, C., Boekel, J., Andersson, H., Nilsson, I., White, S.H., and von Heijne, G. (2005) Recognition of transmembrane helices by the endoplasmic reticulum translocon. Nature 433, 377–381.PubMedCrossRefGoogle Scholar
  23. 23.
    Bernsel, A., Viklund, H., Falk, J., Lindahl, E., von Heijne, G., and Elofsson, A. (2008) Prediction of membrane-protein topology from first principles. Proceedings of the National Academy of Sciences of the United States of America 105, 7177–7181.PubMedCrossRefGoogle Scholar
  24. 24.
    Altschul, S.F., Gish, W., Miller, W., Myers, E.W., and Lipman, D.J. (1990) A basic local alignment search tool. Journal of Molecular Biology 215, 403–410.PubMedGoogle Scholar
  25. 25.
    Persson, B. and Argos, P. (1997) Prediction of membrane protein topology utilizing multiple sequence alignments. Journal of Protein Chemistry 16, 453–457.PubMedCrossRefGoogle Scholar
  26. 26.
    Jones, D.T. (2007) Improving the accuracy of transmembrane protein topology prediction using evolutionary information. Bioinformatics 23, 538–544.PubMedCrossRefGoogle Scholar
  27. 27.
    Viklund, H. and Elofsson, A. (2008) OCTOPUS: improving topology prediction by two-track ANN-based preference scores and an extended topological grammar. Bioinformatics 24, 1662–1668.PubMedCrossRefGoogle Scholar
  28. 28.
    Käll, L., Krogh, A., and Sonnhammer, E.L.L. (2005) An HMM posterior decoder for sequence feature prediction that includes homology information. Bioinformatics 21 (S1), i251–i257.PubMedCrossRefGoogle Scholar
  29. 29.
    Drew, D., Sjostrand, D., Nilsson, J., Urbig, T., Chin, C., de Gier, J.W., and von Heijne, G. (2002) Rapid topology mapping of Escherichia coli inner-membrane proteins by prediction and PhoA/GFP fusion analysis. Proceedings of the National Academy of Sciences of the United States of America 99, 2690–2695.PubMedCrossRefGoogle Scholar
  30. 30.
    Melén, K., Krogh, A., and von Heijne, G. (2003) Reliability measures for membrane protein topology prediction algorithms. Journal of Molecular Biology 327, 735–744.PubMedCrossRefGoogle Scholar
  31. 31.
    Daley, D.O., Rapp, M., Granseth, E., Melen, K., Drew, D., and von Heijne, G. (2005) Global topology analysis of the Escherichia coli inner membrane proteome. Science 308, 1321–1323.PubMedCrossRefGoogle Scholar
  32. 32.
    Kim, H., Melen, K., Osterberg, M., and von Heijne, G. (2006) A global topology map of the Saccharomyces cerevisiae membrane proteome. Proceedings of the National Academy of Sciences of the United States of America 103, 11142.PubMedCrossRefGoogle Scholar
  33. 33.
    Kauko, A., Illergård, K., and Elofsson, A. (2008) Coils in the membrane core are conserved and functionally important. Journal of Molecular Biology 380, 170–180.PubMedCrossRefGoogle Scholar
  34. 34.
    Granseth, E., Viklund, H., and Elofsson, A. (2006) ZPRED: predicting the distance to the membrane center for residues in alpha-helical membrane proteins. Bioinformatics 22, e191–e196.PubMedCrossRefGoogle Scholar
  35. 35.
    Papaloukas, C., Granseth, E., Viklund, H., and Elofsson, A. (2008) Estimating the length of transmembrane helices using Z-coordinate predictions. Protein Science 17, 271–278.PubMedCrossRefGoogle Scholar
  36. 36.
    Martelli, P.L., Fariselli, P., Krogh, A., and Casadio, R. (2002) A sequence-profile-based HMM for predicting and discriminating beta barrel membrane proteins. Bioinformatics 18 Suppl 1, S46–S53.PubMedCrossRefGoogle Scholar
  37. 37.
    Zhai, Y. and Saier, M.H., Jr. (2002) The beta-barrel finder (BBF) program, allowing identification of outer membrane beta-barrel proteins encoded within prokaryotic genomes. Protein Science 11, 2196–2207.PubMedCrossRefGoogle Scholar
  38. 38.
    von Heijne, G. (1986) A new method for predicting signal sequence cleavage sites. Nucleic Acids Research 14, 4683–4690.CrossRefGoogle Scholar
  39. 39.
    Nielsen, H., Engelbrecht, J., Brunak, S., and von Heijne, G. (1997) Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites. Protein Engineering 10, 1–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Bendtsen, J.D., Nielsen, H., von Heijne, G., and Brunak, S. (2004) Improved prediction of signal peptides: SignalP 3.0. Journal of Molecular Biology 340, 783–795.PubMedCrossRefGoogle Scholar
  41. 41.
    Nielsen, H. and Krogh, A. (1998) Prediction of signal peptides and signal anchors by a hidden Markov model. Proceedings of the International Conference on Intelligent Systems for Molecular Biology 6, 122–130.Google Scholar
  42. 42.
    Chou, K.C. (2001) Prediction of protein signal sequences and their cleavage sites. Proteins 42, 136–139.PubMedCrossRefGoogle Scholar
  43. 43.
    Vert, J.P. (2002) Support vector machine prediction of signal peptide cleavage site using a new class of kernels for strings. In R.B. Altman, A.K. Dunker, L. Hunter, K. Lauerdale, and T.E. Klein, editors, Proceedings of the Pacific Symposium on Biocomputing, pages 649–660. World Scientific, SingaporeGoogle Scholar
  44. 44.
    Kahsay, R.Y., Gao, G., and Liao, L. (2005) Discri­minating transmembrane proteins from signal peptides using svm-Fisher approach. In ICMLA ‘05: Proceedings of the Fourth Inter­na­tional Conference on Machine Learning and Applications, pages 151–155. IEEE Computer Society, Washington, DC, USA, ISBN 0-7695-2495-8.CrossRefGoogle Scholar
  45. 45.
    Käll, L., Krogh, A., and Sonnhammer, E.L.L. (2007) Advantages of combined transmembrane topology and signal peptide prediction – the Phobius web server. Nucleic Acids Research 35, W429.PubMedCrossRefGoogle Scholar
  46. 46.
    Viklund, H., Bernsel, A., Skwark, M., and Elofsson, A. (2008) SPOCTOPUS: a combined predictor of signal peptides and membrane protein topology. Bioinformatics 24, 2928.PubMedCrossRefGoogle Scholar
  47. 47.
    Viklund, H. and Elofsson, A. (2004) Best α-helical transmembrane protein topology predictions are achieved using hidden Markov models and evolutionary information. Protein Science 3, 1908–1917.CrossRefGoogle Scholar
  48. 48.
    von Heijne, G. (1983) Patterns of amino acids near signal-sequence cleavage sites. European Journal of Biochemistry 133, 17–21.CrossRefGoogle Scholar
  49. 49.
    Perlman, D. and Halvorson, H.O. (1983) A putative signal peptidase recognition site and sequence in eukaryotic and prokaryotic signal peptides. Journal of Molecular Biology 167, 391–409.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Lukas Käll
    • 1
  1. 1.Department of Biochemistry and Biophysics, Center for Biomembrane Research and Stockholm Bioinformatics CenterStockholm UniversityStockholmSweden

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