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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Aug 29;92(18):8368–8372. doi: 10.1073/pnas.92.18.8368

Periodic variation in side-chain polarities of T-cell antigenic peptides correlates with their structure and activity.

J L Cornette 1, H Margalit 1, J A Berzofsky 1, C DeLisi 1
PMCID: PMC41158  PMID: 7667297

Abstract

We present an analysis that synthesizes information on the sequence, structure, and motifs of antigenic peptides, which previously appeared to be in conflict. Fourier analysis of T-cell antigenic peptides indicates a periodic variation in amino acid polarities of 3-3.6 residues per period, suggesting an amphipathic alpha-helical structure. However, the diffraction patterns of major histocompatibility complex (MHC) molecules indicate that their ligands are in an extended non-alpha-helical conformation. We present two mutually consistent structural explanations for the source of the alpha-helical periodicity, based on an observation that the side chains of MHC-bound peptides generally partition with hydrophobic (hydrophilic) side chains pointing into (out of) the cleft. First, an analysis of haplotype-dependent peptide motifs indicates that the locations of their defining residues tend to force a period 3-4 variation in hydrophobicity along the peptide sequence, in a manner consistent with the spacing of pockets in the MHC. Second, recent crystallographic determination of the structure of a peptide bound to a class II MHC molecule reveals an extended but regularly twisted peptide with a rotation angle of about 130 degrees. We show that similar structures with rotation angles of 100-130 degrees are energetically acceptable and also span the length of the MHC cleft. These results provide a sound physical chemical and structural basis for the existence of a haplotype-independent antigenic motif which can be particularly important in limiting the search time for antigenic peptides.

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Selected References

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  1. Adzhubei A. A., Sternberg M. J. Left-handed polyproline II helices commonly occur in globular proteins. J Mol Biol. 1993 Jan 20;229(2):472–493. doi: 10.1006/jmbi.1993.1047. [DOI] [PubMed] [Google Scholar]
  2. Altuvia Y., Berzofsky J. A., Rosenfeld R., Margalit H. Sequence features that correlate with MHC restriction. Mol Immunol. 1994 Jan;31(1):1–19. doi: 10.1016/0161-5890(94)90133-3. [DOI] [PubMed] [Google Scholar]
  3. Bastin J., Rothbard J., Davey J., Jones I., Townsend A. Use of synthetic peptides of influenza nucleoprotein to define epitopes recognized by class I-restricted cytotoxic T lymphocytes. J Exp Med. 1987 Jun 1;165(6):1508–1523. doi: 10.1084/jem.165.6.1508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bernstein F. C., Koetzle T. F., Williams G. J., Meyer E. F., Jr, Brice M. D., Rodgers J. R., Kennard O., Shimanouchi T., Tasumi M. The Protein Data Bank: a computer-based archival file for macromolecular structures. J Mol Biol. 1977 May 25;112(3):535–542. doi: 10.1016/s0022-2836(77)80200-3. [DOI] [PubMed] [Google Scholar]
  5. Cease K. B., Margalit H., Cornette J. L., Putney S. D., Robey W. G., Ouyang C., Streicher H. Z., Fischinger P. J., Gallo R. C., DeLisi C. Helper T-cell antigenic site identification in the acquired immunodeficiency syndrome virus gp120 envelope protein and induction of immunity in mice to the native protein using a 16-residue synthetic peptide. Proc Natl Acad Sci U S A. 1987 Jun;84(12):4249–4253. doi: 10.1073/pnas.84.12.4249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cornette J. L., Cease K. B., Margalit H., Spouge J. L., Berzofsky J. A., DeLisi C. Hydrophobicity scales and computational techniques for detecting amphipathic structures in proteins. J Mol Biol. 1987 Jun 5;195(3):659–685. doi: 10.1016/0022-2836(87)90189-6. [DOI] [PubMed] [Google Scholar]
  7. Corr M., Boyd L. F., Padlan E. A., Margulies D. H. H-2Dd exploits a four residue peptide binding motif. J Exp Med. 1993 Dec 1;178(6):1877–1892. doi: 10.1084/jem.178.6.1877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. DeLisi C., Berzofsky J. A. T-cell antigenic sites tend to be amphipathic structures. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7048–7052. doi: 10.1073/pnas.82.20.7048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eisenberg D., Weiss R. M., Terwilliger T. C. The hydrophobic moment detects periodicity in protein hydrophobicity. Proc Natl Acad Sci U S A. 1984 Jan;81(1):140–144. doi: 10.1073/pnas.81.1.140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fremont D. H., Matsumura M., Stura E. A., Peterson P. A., Wilson I. A. Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb. Science. 1992 Aug 14;257(5072):919–927. doi: 10.1126/science.1323877. [DOI] [PubMed] [Google Scholar]
  11. Good M. F., Maloy W. L., Lunde M. N., Margalit H., Cornette J. L., Smith G. L., Moss B., Miller L. H., Berzofsky J. A. Construction of synthetic immunogen: use of new T-helper epitope on malaria circumsporozoite protein. Science. 1987 Feb 27;235(4792):1059–1062. doi: 10.1126/science.2434994. [DOI] [PubMed] [Google Scholar]
  12. Gotch F., Rothbard J., Howland K., Townsend A., McMichael A. Cytotoxic T lymphocytes recognize a fragment of influenza virus matrix protein in association with HLA-A2. 1987 Apr 30-May 6Nature. 326(6116):881–882. doi: 10.1038/326881a0. [DOI] [PubMed] [Google Scholar]
  13. Hobohm U., Scharf M., Schneider R., Sander C. Selection of representative protein data sets. Protein Sci. 1992 Mar;1(3):409–417. doi: 10.1002/pro.5560010313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kurata A., Palker T. J., Streilein R. D., Scearce R. M., Haynes B. F., Berzofsky J. A. Immunodominant sites of human T cell lymphotropic virus type 1 envelope protein for murine helper T cells. J Immunol. 1989 Sep 15;143(6):2024–2030. [PubMed] [Google Scholar]
  15. Lamb J. R., Ivanyi J., Rees A. D., Rothbard J. B., Howland K., Young R. A., Young D. B. Mapping of T cell epitopes using recombinant antigens and synthetic peptides. EMBO J. 1987 May;6(5):1245–1249. doi: 10.1002/j.1460-2075.1987.tb02360.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Leighton J., Sette A., Sidney J., Appella E., Ehrhardt C., Fuchs S., Adorini L. Comparison of structural requirements for interaction of the same peptide with I-Ek and I-Ed molecules in the activation of MHC class II-restricted T cells. J Immunol. 1991 Jul 1;147(1):198–204. [PubMed] [Google Scholar]
  17. Madden D. R., Garboczi D. N., Wiley D. C. The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2. Cell. 1993 Nov 19;75(4):693–708. doi: 10.1016/0092-8674(93)90490-h. [DOI] [PubMed] [Google Scholar]
  18. Madden D. R., Gorga J. C., Strominger J. L., Wiley D. C. The structure of HLA-B27 reveals nonamer self-peptides bound in an extended conformation. Nature. 1991 Sep 26;353(6342):321–325. doi: 10.1038/353321a0. [DOI] [PubMed] [Google Scholar]
  19. Madden D. R., Gorga J. C., Strominger J. L., Wiley D. C. The three-dimensional structure of HLA-B27 at 2.1 A resolution suggests a general mechanism for tight peptide binding to MHC. Cell. 1992 Sep 18;70(6):1035–1048. doi: 10.1016/0092-8674(92)90252-8. [DOI] [PubMed] [Google Scholar]
  20. Margalit H., Spouge J. L., Cornette J. L., Cease K. B., Delisi C., Berzofsky J. A. Prediction of immunodominant helper T cell antigenic sites from the primary sequence. J Immunol. 1987 Apr 1;138(7):2213–2229. [PubMed] [Google Scholar]
  21. Meister G. E., Roberts C. G., Berzofsky J. A., De Groot A. S. Two novel T cell epitope prediction algorithms based on MHC-binding motifs; comparison of predicted and published epitopes from Mycobacterium tuberculosis and HIV protein sequences. Vaccine. 1995 Apr;13(6):581–591. doi: 10.1016/0264-410x(94)00014-e. [DOI] [PubMed] [Google Scholar]
  22. Rammensee H. G., Friede T., Stevanoviíc S. MHC ligands and peptide motifs: first listing. Immunogenetics. 1995;41(4):178–228. doi: 10.1007/BF00172063. [DOI] [PubMed] [Google Scholar]
  23. Reyes V. E., Fowlie E. J., Lu S., Phillips L., Chin L. T., Humphreys R. E., Lew R. A. Comparison of three related methods to select T cell-presented sequences of protein antigens. Mol Immunol. 1990 Oct;27(10):1021–1027. doi: 10.1016/0161-5890(90)90125-j. [DOI] [PubMed] [Google Scholar]
  24. Rothbard J. B., Taylor W. R. A sequence pattern common to T cell epitopes. EMBO J. 1988 Jan;7(1):93–100. doi: 10.1002/j.1460-2075.1988.tb02787.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sette A., Buus S., Appella E., Smith J. A., Chesnut R., Miles C., Colon S. M., Grey H. M. Prediction of major histocompatibility complex binding regions of protein antigens by sequence pattern analysis. Proc Natl Acad Sci U S A. 1989 May;86(9):3296–3300. doi: 10.1073/pnas.86.9.3296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Silver M. L., Guo H. C., Strominger J. L., Wiley D. C. Atomic structure of a human MHC molecule presenting an influenza virus peptide. Nature. 1992 Nov 26;360(6402):367–369. doi: 10.1038/360367a0. [DOI] [PubMed] [Google Scholar]
  27. Spouge J. L., Guy H. R., Cornette J. L., Margalit H., Cease K., Berzofsky J. A., DeLisi C. Strong conformational propensities enhance T cell antigenicity. J Immunol. 1987 Jan 1;138(1):204–212. [PubMed] [Google Scholar]
  28. Stern L. J., Brown J. H., Jardetzky T. S., Gorga J. C., Urban R. G., Strominger J. L., Wiley D. C. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature. 1994 Mar 17;368(6468):215–221. doi: 10.1038/368215a0. [DOI] [PubMed] [Google Scholar]
  29. Stille C. J., Thomas L. J., Reyes V. E., Humphreys R. E. Hydrophobic strip-of-helix algorithm for selection of T cell-presented peptides. Mol Immunol. 1987 Oct;24(10):1021–1027. doi: 10.1016/0161-5890(87)90068-x. [DOI] [PubMed] [Google Scholar]
  30. Takahashi H., Cohen J., Hosmalin A., Cease K. B., Houghten R., Cornette J. L., DeLisi C., Moss B., Germain R. N., Berzofsky J. A. An immunodominant epitope of the human immunodeficiency virus envelope glycoprotein gp160 recognized by class I major histocompatibility complex molecule-restricted murine cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1988 May;85(9):3105–3109. doi: 10.1073/pnas.85.9.3105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Zamvil S. S., Mitchell D. J., Moore A. C., Kitamura K., Steinman L., Rothbard J. B. T-cell epitope of the autoantigen myelin basic protein that induces encephalomyelitis. Nature. 1986 Nov 20;324(6094):258–260. doi: 10.1038/324258a0. [DOI] [PubMed] [Google Scholar]
  32. Zhang W., Young A. C., Imarai M., Nathenson S. G., Sacchettini J. C. Crystal structure of the major histocompatibility complex class I H-2Kb molecule containing a single viral peptide: implications for peptide binding and T-cell receptor recognition. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8403–8407. doi: 10.1073/pnas.89.17.8403. [DOI] [PMC free article] [PubMed] [Google Scholar]

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