, Volume 41, Issue 5, pp 257–262

Self peptides bound by HLA class I molecules are derived from highly conserved regions of a set of evolutionarily conserved proteins

  • Austin L. Hughes
  • Marianne K. Hughes


An evolutionary analysis of self peptides reported to be bound by HLA class I molecules showed that these peptides are largely derived from proteins that have been highly conserved in the history of mammals. These proteins also often have universal tissue expression and have a higher than average frequency of highly hydrophilic residues. The peptides themselves are generally still more highly conserved than the source proteins and have a higher frequency of highly hydrophobic residues, evidently often derived from conserved hydrophobic cores of the source proteins. These results suggest that the mechanism by which peptides are derived for MHC presentation may preferentially select peptides from conserved protein regions. In the case of parasite-derived peptides, such a mechanism would be adaptive in that it would reduce the likelihood of escape mutants.


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  1. Auger, I. C. Computational techniques to predict amphipathichelical segments. In R. M. Epand, (ed.): The Amphipathic Helix, pp. 7–19, CRC Press, Boca Raton, 1993Google Scholar
  2. Berke, G. The binding and lysis of target cells by cytotoxic lymphocytes: molecular and cellular aspects. Annu Rev Immunol 12: 735–773, 1994Google Scholar
  3. DiBrino, M., Parker, K. C., Shiloach, J., Turner, R. V., Tsuchida, T., Garfield, M., Biddison, W. E., and Coligan, J. E. Endogenous peptides with distinct amino acid anchor residue motifs bind to HLA-A1 and HLA-B8. J Immunol 152: 620–631, 1994Google Scholar
  4. Driscoll, J., Brown, M. G., Finley, D., and Monaco, J. J. MHC-linked LMP gene products specifically after peptidase activities of the proteasome. Nature 365: 262–264, 1993Google Scholar
  5. Engelhard, V. H. Structure of peptides associated with class I MHC molecules. Curr Opin Immunol 6: 13–23, 1994Google Scholar
  6. Engelhard, V. H., Appella, E., Benjamin, D. C., Bodnar, W. M., Cox, A. L., Chen, Y., Henderson, R. A., Huczko, E. L., Michel, H., Sakaguchi, K., Shabanowitz, J., Sevilir, N., Slingluff, C. L., and Hunt, D. F. Mass spectrometric analysis of peptides associated with the human class I MHC molecules HLA-A2 and HLA-B7 and identification of features that determine binding. Chem Immunol 57: 39–62, 1993Google Scholar
  7. Fidock, D. A., Gras-Masse, H., Lepers, J.-P., Brahami, K., Benmohamed, L., Melloak, S., Guerin-Marchand, C., Londaro, A., Raharimalala, L., Meis, J. F. G. M., Langsley, G., Roussilhon, C., Tartar, A., and Druilhe, P. Plasmodium falciparum liver stage antigen-1 is well conserved and contains potent B and T cell determinants. J Immunol 154: 190–204, 1994Google Scholar
  8. Gaczynska, M., Rock, K. L., and Goldberg, A. L. λ-interferons and expression of MHC genes regulate protein hydrolysis by proteasomes. Nature 365: 264–267, 1993Google Scholar
  9. Germain, R. N. MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell 76: 287–299, 1994Google Scholar
  10. Goldberg, A. L. and Rock, K. L. Proteolysis, proteasomes, and antigen presentation. Nature 357: 375–379, 1992Google Scholar
  11. Guo, H.-C., Jardetzky, T. S., Garret, T. P. J., Lane, W. S., Strominger, J. L., and Wiley, D. C. Different length peptides bind to HLA-Aw68 similarly at their ends but bulge out in the middle. Nature 360: 364–367, 1992Google Scholar
  12. Harris, P. E., Colovai, A., Lin, Z., Dalla Favera, R., and Sucia-Foca, N. Naturally processed HLA class I bound peptides from c-myc-transfected cells reveal allele-specific motifs. J Immunol 151: 5966–5974, 1993Google Scholar
  13. Hill, A. V. S., Allsopp, C. E. M., Kwiatkowski, D., Anstey, N. M., Twumasi, P., Rowe, P. A., Bennett, S., Brewster, D., McMichael, A. J., and Greenwood, B. M. Common West African HLA antigens are associated with protection from severe malaria. Nature 352: 595–600, 1991Google Scholar
  14. Hill, A. V. S., Elvin, J., Willis, A. C., Aidoo, M., Allsopp, C. E. M., Gotch, F. M., Gao, X. M., Takiguchi, M., Greenwood, B. M., Townsend, A. R. M., McMichael, A. J., and Whittle, H. C. Molecular analysis of the association of HLA-B53 and resistance to severe malaria. Nature 360: 434–439, 1992Google Scholar
  15. Huczko, E. L., Bodnar, W. M., Benjamin, D., Sakaguchi, K., Zhu, N. Z., Shabanowitz, J., Henderson, R. A., Appells, E., Hunt, D. F., and Engelhard, V. H. Characteristics of endogenous peptides eluted from the class I MHC molecule HLA-B1 determined by mass spectrometry and computer modeling. J Immunol 151: 2572–2587, 1993Google Scholar
  16. Hughes, A. L. and Nei, M. Evolution of the major histocompatibility complex: independent origin of nonclassical class I genes in different groups of mammals. Mol Biol Evol 6: 559–579, 1989Google Scholar
  17. Hughes, A. L. and Nei, M. Evolutionary relationships of class II major-histocompatibility-complex genes in mammals. Mol Biol Evol 7: 491–514, 1990Google Scholar
  18. Hunt, D. F. and Engelhard, V. H. HLA-A2.1 associated peptides from a mutant cell line: a second pathway of antigen presentation. Science 255: 1264–1266, 1992Google Scholar
  19. Hunt, D. F., Henderson, R. A., Shabanowitz, J., Sakaguchi, K., Michel, H., Sevilir, N., Cox, A., Appella, E., and Engelhard, V. H. Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 255: 1261–1263, 1992PubMedGoogle Scholar
  20. Jardetzky, T. S., Lane, W. S., Robinson, R. A., Madden, D. R., and Wiley, D. C. Identification of self peptides bound to purified HLA-B27. Nature 353: 326–329, 1991Google Scholar
  21. Johnson, R. P., Tocha, A., Yang, L., Mazzara, G. P., Panicali, D. L., Buchanan, T. M., and Walker, B. D. HIV-1 gag-specific cytotoxic T lymphocytes recognize multiple highly conserved epitopes. J Immunol 147: 1512–1521, 1991Google Scholar
  22. Kimura, M. The Neutral Theory of Molecular Evolution, Cambridge University, Press, Cambridge, 1983Google Scholar
  23. Margalit, H., Sponge, J. L., Cornette, J. L., Cease, K. B., Delisi, C., and Berzofsky, J. A. Prediction of immunodominant helper T cell antigenic sites from the primary sequence. J Immunol 138: 2213–2229, 1987Google Scholar
  24. Monaco, J. J. A molecular model of MHC class-I-restricted antigen processing. Immunol Today 13: 173–178, 1992Google Scholar
  25. Neefjes, J. J., Momburg, F., and Hammerling, G. J. Selective and ATP-dependent translocation of peptides by the MHC-encoded transporters. Science 261: 769–771, 1993Google Scholar
  26. Powis, S. J., Deverson, E. V., Coadwell, W. J., Cirnela, A., Huskisson, N. S., Smith, H., Butcher, G. W., and Howard, J. C. Effect of polymorphism of an MHC-linked transporter on the peptides assembled in a class I molecule. Nature 357: 211–215, 1992Google Scholar
  27. Shepherd, J. C., Schumacher, T. N. M., Ashton-Rickardt, P. G., Imaeda, S., Ploegh, H. L., Janeway, C. A., Jr., and Tonegawa, S. TAP1-dependent peptide translocation in vitro is ATP dependent and peptide selective. Cell 74: 577–584, 1993Google Scholar
  28. Townsend, A. R. M., Gocth, F. M., and Davey,J. Cytotoxic T cells recognize fragments of the influenza nucleoprotein. Cell 42: 417–467, 1985Google Scholar
  29. Townsend, A., Ohlen, C., Bastin, J., Ljunggren, H. G., Foster, L., and Kavre, K. Association of class I major histocompatibility heavy and light chains induced by viral peptides. Nature 340: 443–448, 1989Google Scholar
  30. Vriz, S., Taylor, M., and Mechali, M. Differential expression of two Xenopus c-myc proto-oncogenes during development. EMBO J 8: 4091–4097, 1989Google Scholar
  31. Wyckoff, E., Natalie, D., Nolan, J. M., Lee, M., and Hsieh, T.-S. Structure of the Drosophila DNA topoisomerase II gene: nucleotide sequence and homology among topoisomerases II. J Mol Biol 205: 1–13, 1989Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Austin L. Hughes
    • 1
  • Marianne K. Hughes
    • 2
  1. 1.Department of Biology, 208 Mueller LaboratoryThe Pennsylvania State UniversityUniversity ParkUSA
  2. 2.Institute of Molecular GeneticsThe Pennsylvania State UniversityUniversity ParkUSA

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