Skip to main content
NCBI home page
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 Jul 3;92(14):6567–6571. doi: 10.1073/pnas.92.14.6567

Naturally processed peptides from two disease-resistance-associated HLA-DR13 alleles show related sequence motifs and the effects of the dimorphism at position 86 of the HLA-DR beta chain.

M P Davenport 1, C L Quinn 1, R M Chicz 1, B N Green 1, A C Willis 1, W S Lane 1, J I Bell 1, A V Hill 1
PMCID: PMC41559  PMID: 7604034

Abstract

HLA-DR13 has been associated with resistance to two major infectious diseases of humans. To investigate the peptide binding specificity of two HLA-DR13 molecules and the effects of the Gly/Val dimorphism at position 86 of the HLA-DR beta chain on natural peptide ligands, these peptides were acid-eluted from immunoaffinity-purified HLA-DRB1*1301 and -DRB1*1302, molecules that differ only at this position. The eluted peptides were subjected to pool sequencing or individual peptide sequencing by tandem MS or Edman microsequencing. Sequences were obtained for 23 peptides from nine source proteins. Three pool sequences for each allele and the sequences of individual peptides were used to define binding motifs for each allele. Binding specificities varied only at the primary hydrophobic anchor residue, the differences being a preference for the aromatic amino acids Tyr and Phe in DRB1*1302 and a preference for Val in DRB1*1301. Synthetic analogues of the eluted peptides showed allele specificity in their binding to purified HLA-DR, and Ala-substituted peptides were used to identify the primary anchor residues for binding. The failure of some peptides eluted from DRB1*1302 (those that use aromatic amino acids as primary anchors) to bind to DRB1*1301 confirmed the different preferences for peptide anchor residues conferred by the Gly-->Val change at position 86. These data suggest a molecular basis for the differential associations of HLA-DRB1*1301 and DRB1*1302 with resistance to severe malaria and clearance of hepatitis B virus infection.

Full text

PDF
6567

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Apple R. J., Erlich H. A., Klitz W., Manos M. M., Becker T. M., Wheeler C. M. HLA DR-DQ associations with cervical carcinoma show papillomavirus-type specificity. Nat Genet. 1994 Feb;6(2):157–162. doi: 10.1038/ng0294-157. [DOI] [PubMed] [Google Scholar]
  2. Bell J. I., Denney D., Jr, Foster L., Belt T., Todd J. A., McDevitt H. O. Allelic variation in the DR subregion of the human major histocompatibility complex. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6234–6238. doi: 10.1073/pnas.84.17.6234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown J. H., Jardetzky T. S., Gorga J. C., Stern L. J., Urban R. G., Strominger J. L., Wiley D. C. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature. 1993 Jul 1;364(6432):33–39. doi: 10.1038/364033a0. [DOI] [PubMed] [Google Scholar]
  4. Busch R., Hill C. M., Hayball J. D., Lamb J. R., Rothbard J. B. Effect of natural polymorphism at residue 86 of the HLA-DR beta chain on peptide binding. J Immunol. 1991 Aug 15;147(4):1292–1298. [PubMed] [Google Scholar]
  5. Buus S., Sette A., Colon S. M., Jenis D. M., Grey H. M. Isolation and characterization of antigen-Ia complexes involved in T cell recognition. Cell. 1986 Dec 26;47(6):1071–1077. doi: 10.1016/0092-8674(86)90822-6. [DOI] [PubMed] [Google Scholar]
  6. Chicz R. M., Urban R. G., Gorga J. C., Vignali D. A., Lane W. S., Strominger J. L. Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles. J Exp Med. 1993 Jul 1;178(1):27–47. doi: 10.1084/jem.178.1.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chicz R. M., Urban R. G., Lane W. S., Gorga J. C., Stern L. J., Vignali D. A., Strominger J. L. Predominant naturally processed peptides bound to HLA-DR1 are derived from MHC-related molecules and are heterogeneous in size. Nature. 1992 Aug 27;358(6389):764–768. doi: 10.1038/358764a0. [DOI] [PubMed] [Google Scholar]
  8. Demotz S., Barbey C., Corradin G., Amoroso A., Lanzavecchia A. The set of naturally processed peptides displayed by DR molecules is tuned by polymorphism of residue 86. Eur J Immunol. 1993 Feb;23(2):425–432. doi: 10.1002/eji.1830230219. [DOI] [PubMed] [Google Scholar]
  9. Falk K., Rötzschke O., Stevanović S., Jung G., Rammensee H. G. Pool sequencing of natural HLA-DR, DQ, and DP ligands reveals detailed peptide motifs, constraints of processing, and general rules. Immunogenetics. 1994;39(4):230–242. doi: 10.1007/BF00188785. [DOI] [PubMed] [Google Scholar]
  10. Gorski J., Mach B. Polymorphism of human Ia antigens: gene conversion between two DR beta loci results in a new HLA-D/DR specificity. Nature. 1986 Jul 3;322(6074):67–70. doi: 10.1038/322067a0. [DOI] [PubMed] [Google Scholar]
  11. Hammer J., Takacs B., Sinigaglia F. Identification of a motif for HLA-DR1 binding peptides using M13 display libraries. J Exp Med. 1992 Oct 1;176(4):1007–1013. doi: 10.1084/jem.176.4.1007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hill A. V., Allsopp C. E., Kwiatkowski D., Anstey N. M., Twumasi P., Rowe P. A., Bennett S., Brewster D., McMichael A. J., Greenwood B. M. Common west African HLA antigens are associated with protection from severe malaria. Nature. 1991 Aug 15;352(6336):595–600. doi: 10.1038/352595a0. [DOI] [PubMed] [Google Scholar]
  13. Hunt D. F., Michel H., Dickinson T. A., Shabanowitz J., Cox A. L., Sakaguchi K., Appella E., Grey H. M., Sette A. Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad. Science. 1992 Jun 26;256(5065):1817–1820. doi: 10.1126/science.1319610. [DOI] [PubMed] [Google Scholar]
  14. Krieger J. I., Karr R. W., Grey H. M., Yu W. Y., O'Sullivan D., Batovsky L., Zheng Z. L., Colón S. M., Gaeta F. C., Sidney J. Single amino acid changes in DR and antigen define residues critical for peptide-MHC binding and T cell recognition. J Immunol. 1991 Apr 1;146(7):2331–2340. [PubMed] [Google Scholar]
  15. Kropshofer H., Max H., Müller C. A., Hesse F., Stevanovic S., Jung G., Kalbacher H. Self-peptide released from class II HLA-DR1 exhibits a hydrophobic two-residue contact motif. J Exp Med. 1992 Jun 1;175(6):1799–1803. doi: 10.1084/jem.175.6.1799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kubo R. T., Sette A., Grey H. M., Appella E., Sakaguchi K., Zhu N. Z., Arnott D., Sherman N., Shabanowitz J., Michel H. Definition of specific peptide motifs for four major HLA-A alleles. J Immunol. 1994 Apr 15;152(8):3913–3924. [PubMed] [Google Scholar]
  17. Marshall K. W., Liu A. F., Canales J., Perahia B., Jorgensen B., Gantzos R. D., Aguilar B., Devaux B., Rothbard J. B. Role of the polymorphic residues in HLA-DR molecules in allele-specific binding of peptide ligands. J Immunol. 1994 May 15;152(10):4946–4957. [PubMed] [Google Scholar]
  18. Newton-Nash D. K., Eckels D. D. Differential effect of polymorphism at HLA-DR1 beta-chain positions 85 and 86 on binding and recognition of DR1-restricted antigenic peptides. J Immunol. 1993 Mar 1;150(5):1813–1821. [PubMed] [Google Scholar]
  19. Nowak M. A., Tarczy-Hornoch K., Austyn J. M. The optimal number of major histocompatibility complex molecules in an individual. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10896–10899. doi: 10.1073/pnas.89.22.10896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Roche P. A., Cresswell P. High-affinity binding of an influenza hemagglutinin-derived peptide to purified HLA-DR. J Immunol. 1990 Mar 1;144(5):1849–1856. [PubMed] [Google Scholar]
  21. Rudensky AYu, Preston-Hurlburt P., al-Ramadi B. K., Rothbard J., Janeway C. A., Jr Truncation variants of peptides isolated from MHC class II molecules suggest sequence motifs. Nature. 1992 Oct 1;359(6394):429–431. doi: 10.1038/359429a0. [DOI] [PubMed] [Google Scholar]
  22. Thursz M. R., Kwiatkowski D., Allsopp C. E., Greenwood B. M., Thomas H. C., Hill A. V. Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia. N Engl J Med. 1995 Apr 20;332(16):1065–1069. doi: 10.1056/NEJM199504203321604. [DOI] [PubMed] [Google Scholar]
  23. Tiercy J. M., Gorski J., Bétuel H., Freidel A. C., Gebuhrer L., Jeannet M., Mach B. DNA typing of DRw6 subtypes: correlation with DRB1 and DRB3 allelic sequences by hybridization with oligonucleotide probes. Hum Immunol. 1989 Jan;24(1):1–14. doi: 10.1016/0198-8859(89)90042-6. [DOI] [PubMed] [Google Scholar]
  24. Titus-Trachtenberg E. A., Rickards O., De Stefano G. F., Erlich H. A. Analysis of HLA class II haplotypes in the Cayapa Indians of Ecuador: a novel DRB1 allele reveals evidence for convergent evolution and balancing selection at position 86. Am J Hum Genet. 1994 Jul;55(1):160–167. [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES