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
. 1994 Feb 15;91(4):1534–1538. doi: 10.1073/pnas.91.4.1534

A subset of HLA-B27 molecules contains peptides much longer than nonamers.

R G Urban 1, R M Chicz 1, W S Lane 1, J L Strominger 1, A Rehm 1, M J Kenter 1, F G UytdeHaag 1, H Ploegh 1, B Uchanska-Ziegler 1, A Ziegler 1
PMCID: PMC43194  PMID: 8108441

Abstract

An unusual monoclonal antibody (MARB4) directed against HLA-B27 that reacts with only approximately 5-20% of the cell surface HLA-B27 was used for large-scale purification of these molecules. Subsequent mass spectrometry of HLA-B27-bound peptides showed that the minor MARB4-reactive population contained peptides primarily from 900 to 4000 Da in size (approximately 8-33 amino acid residues), whereas the major HLA-B27 population contained peptides in the mass range of 900-1400 Da (approximately 8-12 amino acid residues). Thus, a subset of HLA-B27 molecules binds to peptides much longer than nonamers. Typical HLA-B27-binding peptides contain arginine in position 2. Further analysis by Edman sequencing of the pooled bound peptides revealed that the major population contained substantial amounts of arginine at positions 1 and 9 (40-50%) and exclusively arginine at position 2, as expected. The minor population of peptides also contained detectable amounts of arginine at these positions, but at the level of only approximately 10%; no marked enrichment at any position was observed. These long HLA-B27-bound peptides could represent either intermediates in the formation of nonamers or adventitiously bound peptides. Lastly, in the TAP2 mutant cell line BM36.1 transfected with HLA-B*2705, MARB4-reactive HLA-B27 molecules were absent from the cell surface, indicating that the peptide transporter was required for delivery of the long peptides. Thus, during the folding of class I heavy chains, peptides of diverse lengths are available and participating.

Full text

PDF
1534

Selected References

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

  1. Androlewicz M. J., Anderson K. S., Cresswell P. Evidence that transporters associated with antigen processing translocate a major histocompatibility complex class I-binding peptide into the endoplasmic reticulum in an ATP-dependent manner. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9130–9134. doi: 10.1073/pnas.90.19.9130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Benjamin R. J., Madrigal J. A., Parham P. Peptide binding to empty HLA-B27 molecules of viable human cells. Nature. 1991 May 2;351(6321):74–77. doi: 10.1038/351074a0. [DOI] [PubMed] [Google Scholar]
  3. Benjamin R., Parham P. Guilt by association: HLA-B27 and ankylosing spondylitis. Immunol Today. 1990 Apr;11(4):137–142. doi: 10.1016/0167-5699(90)90051-a. [DOI] [PubMed] [Google Scholar]
  4. Cerundolo V., Elliott T., Elvin J., Bastin J., Rammensee H. G., Townsend A. The binding affinity and dissociation rates of peptides for class I major histocompatibility complex molecules. Eur J Immunol. 1991 Sep;21(9):2069–2075. doi: 10.1002/eji.1830210915. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Ellis S. A., Taylor C., McMichael A. Recognition of HLA-B27 and related antigen by a monoclonal antibody. Hum Immunol. 1982 Aug;5(1):49–59. doi: 10.1016/0198-8859(82)90030-1. [DOI] [PubMed] [Google Scholar]
  7. Falk K., Rötzschke O., Rammensee H. G. Cellular peptide composition governed by major histocompatibility complex class I molecules. Nature. 1990 Nov 15;348(6298):248–251. doi: 10.1038/348248a0. [DOI] [PubMed] [Google Scholar]
  8. Falk K., Rötzschke O., Stevanović S., Jung G., Rammensee H. G. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature. 1991 May 23;351(6324):290–296. doi: 10.1038/351290a0. [DOI] [PubMed] [Google Scholar]
  9. Garrett T. P., Saper M. A., Bjorkman P. J., Strominger J. L., Wiley D. C. Specificity pockets for the side chains of peptide antigens in HLA-Aw68. Nature. 1989 Dec 7;342(6250):692–696. doi: 10.1038/342692a0. [DOI] [PubMed] [Google Scholar]
  10. Gorga J. C., Madden D. R., Prendergast J. K., Wiley D. C., Strominger J. L. Crystallization and preliminary X-ray diffraction studies of the human major histocompatibility antigen HLA-B27. Proteins. 1992 Jan;12(1):87–90. doi: 10.1002/prot.340120110. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Grosveld F. G., Lund T., Murray E. J., Mellor A. L., Dahl H. H., Flavell R. A. The construction of cosmid libraries which can be used to transform eukaryotic cells. Nucleic Acids Res. 1982 Nov 11;10(21):6715–6732. doi: 10.1093/nar/10.21.6715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hammond S. A., Bollinger R. C., Tobery T. W., Silliciano R. F. Transporter-independent processing of HIV-1 envelope protein for recognition by CD8+ T cells. Nature. 1993 Jul 8;364(6433):158–161. doi: 10.1038/364158a0. [DOI] [PubMed] [Google Scholar]
  14. Hsu V. W., Yuan L. C., Nuchtern J. G., Lippincott-Schwartz J., Hammerling G. J., Klausner R. D. A recycling pathway between the endoplasmic reticulum and the Golgi apparatus for retention of unassembled MHC class I molecules. Nature. 1991 Aug 1;352(6334):441–444. doi: 10.1038/352441a0. [DOI] [PubMed] [Google Scholar]
  15. Jardetzky T. S., Lane W. S., Robinson R. A., Madden D. R., Wiley D. C. Identification of self peptides bound to purified HLA-B27. Nature. 1991 Sep 26;353(6342):326–329. doi: 10.1038/353326a0. [DOI] [PubMed] [Google Scholar]
  16. Kelly A., Powis S. H., Kerr L. A., Mockridge I., Elliott T., Bastin J., Uchanska-Ziegler B., Ziegler A., Trowsdale J., Townsend A. Assembly and function of the two ABC transporter proteins encoded in the human major histocompatibility complex. Nature. 1992 Feb 13;355(6361):641–644. doi: 10.1038/355641a0. [DOI] [PubMed] [Google Scholar]
  17. Latron F., Pazmany L., Morrison J., Moots R., Saper M. A., McMichael A., Strominger J. L. A critical role for conserved residues in the cleft of HLA-A2 in presentation of a nonapeptide to T cells. Science. 1992 Aug 14;257(5072):964–967. doi: 10.1126/science.1380181. [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. Müller C., Ziegler A., Müller G., Schunter F., Wernet P. Monoclonal antibody (Tü48) defining alloantigenic class I determinants specific for HLA-Bw4 and HLA-Aw23,-Aw24 as well as -Aw32. Hum Immunol. 1982 Dec;5(4):269–281. doi: 10.1016/0198-8859(82)90019-2. [DOI] [PubMed] [Google Scholar]
  21. Neefjes J. J., Momburg F., Hämmerling G. J. Selective and ATP-dependent translocation of peptides by the MHC-encoded transporter. Science. 1993 Aug 6;261(5122):769–771. doi: 10.1126/science.8342042. [DOI] [PubMed] [Google Scholar]
  22. Parker K. C., Carreno B. M., Sestak L., Utz U., Biddison W. E., Coligan J. E. Peptide binding to HLA-A2 and HLA-B27 isolated from Escherichia coli. Reconstitution of HLA-A2 and HLA-B27 heavy chain/beta 2-microglobulin complexes requires specific peptides. J Biol Chem. 1992 Mar 15;267(8):5451–5459. [PubMed] [Google Scholar]
  23. Rammensee H. G., Falk K., Rötzschke O. MHC molecules as peptide receptors. Curr Opin Immunol. 1993 Feb;5(1):35–44. doi: 10.1016/0952-7915(93)90078-7. [DOI] [PubMed] [Google Scholar]
  24. Robbins P. A., Lettice L. A., Rota P., Santos-Aguado J., Rothbard J., McMichael A. J., Strominger J. L. Comparison between two peptide epitopes presented to cytotoxic T lymphocytes by HLA-A2. Evidence for discrete locations within HLA-A2. J Immunol. 1989 Dec 15;143(12):4098–4103. [PubMed] [Google Scholar]
  25. Shepherd J. C., Schumacher T. N., Ashton-Rickardt P. G., Imaeda S., Ploegh H. L., Janeway C. A., Jr, Tonegawa S. TAP1-dependent peptide translocation in vitro is ATP dependent and peptide selective. Cell. 1993 Aug 13;74(3):577–584. doi: 10.1016/0092-8674(93)80058-m. [DOI] [PubMed] [Google Scholar]
  26. Stevanović S., Jung G. Multiple sequence analysis: pool sequencing of synthetic and natural peptide libraries. Anal Biochem. 1993 Jul;212(1):212–220. doi: 10.1006/abio.1993.1314. [DOI] [PubMed] [Google Scholar]
  27. Uchańska-Ziegler B., Nössner E., Schenk A., Ziegler A., Schendel D. J. Soluble T cell receptor-like properties of an HLA-B35-specific monoclonal antibody (TU165). Eur J Immunol. 1993 Mar;23(3):734–738. doi: 10.1002/eji.1830230325. [DOI] [PubMed] [Google Scholar]
  28. Volz A., Fonatsch C., Ziegler A. Regional mapping of the gene for autosomal dominant spinocerebellar ataxia (SCA1) by localizing the closely linked D6S89 locus to 6p24.2----p23.05. Cytogenet Cell Genet. 1992;60(1):37–39. doi: 10.1159/000133291. [DOI] [PubMed] [Google Scholar]
  29. Weiss E. H., Kuon W., Dörner C., Lang M., Riethmüller G. Organization, sequence and expression of the HLA-B27 gene: a molecular approach to analyze HLA and disease associations. Immunobiology. 1985 Dec;170(5):367–380. doi: 10.1016/S0171-2985(85)80061-9. [DOI] [PubMed] [Google Scholar]
  30. Ziegler A., Milstein C. A small polypeptide different from beta2-microglobin associated with a human cell surface antigen. Nature. 1979 May 17;279(5710):243–244. doi: 10.1038/279243a0. [DOI] [PubMed] [Google Scholar]
  31. Zweerink H. J., Gammon M. C., Utz U., Sauma S. Y., Harrer T., Hawkins J. C., Johnson R. P., Sirotina A., Hermes J. D., Walker B. D. Presentation of endogenous peptides to MHC class I-restricted cytotoxic T lymphocytes in transport deletion mutant T2 cells. J Immunol. 1993 Mar 1;150(5):1763–1771. [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