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. 1996 Oct;5(10):2080–2088. doi: 10.1002/pro.5560051014

Extended repertoire of permissible peptide ligands for HLA-B*2702.

M Raghavan 1, J A Lebrón 1, J L Johnson 1, P J Bjorkman 1
PMCID: PMC2143273  PMID: 8897608

Abstract

Recognition of self peptides bound to the class I major histocompatibility complex molecule HLA-B27 is thought to trigger proliferation of autoreactive T cells and result in autoimmune arthritic diseases. Previous work from other laboratories established that a predominant feature of endogenous peptides eluted from purified B27 is an arginine at position 2. We studied the binding of peptides containing both natural and unnatural amino acids by the subtype HLA-B*2702, with the goal of gaining insight into peptide binding by this B27 subtype that is associated with susceptibility to arthritic disease. A soluble from of B*2702 was depleted of endogenous peptides. We tested the binding of peptides substituted with cysteine, homocysteine, or an alpha-amino-epsilon-mercapto hexanoic acid side chain (Amh) instead of the naturally occurring arginine at position 2, to determine whether the peptide sulfhydryl residue could be covalently linked to cysteine 67 in the B*2702 binding cleft. Although none of the altered peptide sequences bound covalently to B*2702, the affinities of the homocysteine- and Amh-substituted peptides were close to that of the native peptide sequence. Substitutions at position 2 with other side chains, such as glutamine and methionine, also resulted in peptides that bound with only slightly reduced affinity. These results demonstrate that peptide side chains other than arginine at position 2 can be accomodated within the B*2702 peptide binding site with only minor reductions in affinity. This extended repertoire of permissible B27-binding peptides should be taken into account for a consideration of disease-associated peptide sequences.

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Selected References

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  1. Adorini L., Barnaba V., Bona C., Celada F., Lanzavecchia A., Sercarz E., Suciu-Foca N., Wekerle H. New perspectives on immunointervention in autoimmune diseases. Immunol Today. 1990 Nov;11(11):383–386. doi: 10.1016/0167-5699(90)90148-3. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Bjorkman P. J., Parham P. Structure, function, and diversity of class I major histocompatibility complex molecules. Annu Rev Biochem. 1990;59:253–288. doi: 10.1146/annurev.bi.59.070190.001345. [DOI] [PubMed] [Google Scholar]
  4. Bodmer W. F. The HLA system: introduction. Br Med Bull. 1978 Sep;34(3):213–216. doi: 10.1093/oxfordjournals.bmb.a071500. [DOI] [PubMed] [Google Scholar]
  5. Brewerton D. A., Hart F. D., Nicholls A., Caffrey M., James D. C., Sturrock R. D. Ankylosing spondylitis and HL-A 27. Lancet. 1973 Apr 28;1(7809):904–907. doi: 10.1016/s0140-6736(73)91360-3. [DOI] [PubMed] [Google Scholar]
  6. Chen B. P., Parham P. Direct binding of influenza peptides to class I HLA molecules. Nature. 1989 Feb 23;337(6209):743–745. doi: 10.1038/337743a0. [DOI] [PubMed] [Google Scholar]
  7. Cheng Y., Prusoff W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973 Dec 1;22(23):3099–3108. doi: 10.1016/0006-2952(73)90196-2. [DOI] [PubMed] [Google Scholar]
  8. Fahnestock M. L., Tamir I., Narhi L., Bjorkman P. J. Thermal stability comparison of purified empty and peptide-filled forms of a class I MHC molecule. Science. 1992 Dec 4;258(5088):1658–1662. doi: 10.1126/science.1360705. [DOI] [PubMed] [Google Scholar]
  9. Feltkamp T. E., Khan M. A., Lopez de Castro J. A. The pathogenetic role of HLA-B27. Immunol Today. 1996 Jan;17(1):5–7. doi: 10.1016/0167-5699(96)80559-7. [DOI] [PubMed] [Google Scholar]
  10. Gastinel L. N., Simister N. E., Bjorkman P. J. Expression and crystallization of a soluble and functional form of an Fc receptor related to class I histocompatibility molecules. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):638–642. doi: 10.1073/pnas.89.2.638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gaston J. S. How does HLA-B27 confer susceptibility to inflammatory arthritis? Clin Exp Immunol. 1990 Oct;82(1):1–2. doi: 10.1111/j.1365-2249.1990.tb05394.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hammer R. E., Maika S. D., Richardson J. A., Tang J. P., Taurog J. D. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell. 1990 Nov 30;63(5):1099–1112. doi: 10.1016/0092-8674(90)90512-d. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. 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]
  16. Marrack P., Kappler J. The T cell receptor. Science. 1987 Nov 20;238(4830):1073–1079. doi: 10.1126/science.3317824. [DOI] [PubMed] [Google Scholar]
  17. McMichael A., Bell J. HLA B27: a disease-associated immune response gene. Res Immunol. 1991 Jun-Aug;142(5-6):475–482. doi: 10.1016/0923-2494(91)90050-s. [DOI] [PubMed] [Google Scholar]
  18. Müller R. Determination of affinity and specificity of anti-hapten antibodies by competitive radioimmunoassay. Methods Enzymol. 1983;92:589–601. doi: 10.1016/0076-6879(83)92046-3. [DOI] [PubMed] [Google Scholar]
  19. Parker K. C., DiBrino M., Hull L., Coligan J. E. The beta 2-microglobulin dissociation rate is an accurate measure of the stability of MHC class I heterotrimers and depends on which peptide is bound. J Immunol. 1992 Sep 15;149(6):1896–1904. [PubMed] [Google Scholar]
  20. Qin S. X., Cobbold S., Benjamin R., Waldmann H. Induction of classical transplantation tolerance in the adult. J Exp Med. 1989 Mar 1;169(3):779–794. doi: 10.1084/jem.169.3.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Richardson J. S. The anatomy and taxonomy of protein structure. Adv Protein Chem. 1981;34:167–339. doi: 10.1016/s0065-3233(08)60520-3. [DOI] [PubMed] [Google Scholar]
  22. Ruppert J., Sidney J., Celis E., Kubo R. T., Grey H. M., Sette A. Prominent role of secondary anchor residues in peptide binding to HLA-A2.1 molecules. Cell. 1993 Sep 10;74(5):929–937. doi: 10.1016/0092-8674(93)90472-3. [DOI] [PubMed] [Google Scholar]
  23. Todd J. A., Acha-Orbea H., Bell J. I., Chao N., Fronek Z., Jacob C. O., McDermott M., Sinha A. A., Timmerman L., Steinman L. A molecular basis for MHC class II--associated autoimmunity. Science. 1988 May 20;240(4855):1003–1009. doi: 10.1126/science.3368786. [DOI] [PubMed] [Google Scholar]
  24. Townsend A., Bodmer H. Antigen recognition by class I-restricted T lymphocytes. Annu Rev Immunol. 1989;7:601–624. doi: 10.1146/annurev.iy.07.040189.003125. [DOI] [PubMed] [Google Scholar]
  25. Villadangos J. A., Galocha B., García F., Albar J. P., López de Castro J. A. Modulation of peptide binding by HLA-B27 polymorphism in pockets A and B, and peptide specificity of B*2703. Eur J Immunol. 1995 Aug;25(8):2370–2377. doi: 10.1002/eji.1830250837. [DOI] [PubMed] [Google Scholar]

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