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. 1999 Jul;8(7):1393–1399. doi: 10.1110/ps.8.7.1393

Long-range effects in protein--ligand interactions mediate peptide specificity in the human major histocompatibilty antigen HLA-B27 (B*2701).

S Krebs 1, D Rognan 1, J A López de Castro 1
PMCID: PMC2144368  PMID: 10422827

Abstract

B*2701 differs from all other HLA-B27 subtypes of known peptide specificity in that, among its natural peptide ligands, arginine is not the only allowed residue at peptide position 2. Indeed, B*2701 is unique in binding many peptides with Gln2 in vivo. However, the mutation (Asp74Tyr) responsible for altered selectivity is far away from the B pocket of the peptide binding site to which Gln/Arg2 binds. Here, we present a model that explains this effect. It is proposed that a new rotameric state of the conserved Lys70 is responsible for the unique B*2701 binding motif. This side chain should be either kept away from pocket B through its interaction with Asp74 in most HLA-B27 subtypes, or switched to this pocket if residue 74 is Tyr as in B*2701. Involvement of Lys70 in pocket B would thus allow binding of peptides with Gln2. Binding of Arg2-containing peptides to B*2701 is also possible because Lys70 could adopt another conformation, H-bonded to Asn97, which preserves the same binding mode of Arg2 as in B*2705. This model was experimentally validated by mutating Lys70 into Ala in B*2701. Edman sequencing of the B*2701(K70A) peptide pool showed only Arg2, characteristic of HLA-B27-bound peptides, and no evidence for Gln2. This supports the computational model and demonstrates that allowance of B*2701 for peptides with Gln2 is due to the long-range effect of the polymorphic residue 74 of HLA-B27, by inducing a conformational switch of the conserved Lys70.

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Selected References

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  1. Barnstable C. J., Bodmer W. F., Brown G., Galfre G., Milstein C., Williams A. F., Ziegler A. Production of monoclonal antibodies to group A erythrocytes, HLA and other human cell surface antigens-new tools for genetic analysis. Cell. 1978 May;14(1):9–20. doi: 10.1016/0092-8674(78)90296-9. [DOI] [PubMed] [Google Scholar]
  2. Batalia M. A., Collins E. J. Peptide binding by class I and class II MHC molecules. Biopolymers. 1997;43(4):281–302. doi: 10.1002/(SICI)1097-0282(1997)43:4<281::AID-BIP3>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. Boisgérault F., Tieng V., Stolzenberg M. C., Dulphy N., Khalil I., Tamouza R., Charron D., Toubert A. Differences in endogenous peptides presented by HLA-B*2705 and B*2703 allelic variants. Implications for susceptibility to spondylarthropathies. J Clin Invest. 1996 Dec 15;98(12):2764–2770. doi: 10.1172/JCI119102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Calvo V., Rojo S., López D., Galocha B., López de Castro J. A. Structure and diversity of HLA-B27-specific T cell epitopes. Analysis with site-directed mutants mimicking HLA-B27 subtype polymorphism. J Immunol. 1990 May 15;144(10):4038–4045. [PubMed] [Google Scholar]
  8. Colbert R. A., Rowland-Jones S. L., McMichael A. J., Frelinger J. A. Differences in peptide presentation between B27 subtypes: the importance of the P1 side chain in maintaining high affinity peptide binding to B*2703. Immunity. 1994 May;1(2):121–130. doi: 10.1016/1074-7613(94)90105-8. [DOI] [PubMed] [Google Scholar]
  9. D'Amato M., Fiorillo M. T., Carcassi C., Mathieu A., Zuccarelli A., Bitti P. P., Tosi R., Sorrentino R. Relevance of residue 116 of HLA-B27 in determining susceptibility to ankylosing spondylitis. Eur J Immunol. 1995 Nov;25(11):3199–3201. doi: 10.1002/eji.1830251133. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Fiorillo M. T., Meadows L., D'Amato M., Shabanowitz J., Hunt D. F., Appella E., Sorrentino R. Susceptibility to ankylosing spondylitis correlates with the C-terminal residue of peptides presented by various HLA-B27 subtypes. Eur J Immunol. 1997 Feb;27(2):368–373. doi: 10.1002/eji.1830270205. [DOI] [PubMed] [Google Scholar]
  13. Galocha B., Lamas J. R., Villadangos J. A., Albar J. P., López de Castro J. A. Binding of peptides naturally presented by HLA-B27 to the differentially disease-associated B*2704 and B*2706 subtypes, and to mutants mimicking their polymorphism. Tissue Antigens. 1996 Nov;48(5):509–518. doi: 10.1111/j.1399-0039.1996.tb02664.x. [DOI] [PubMed] [Google Scholar]
  14. García F., Galocha B., Villadangos J. A., Lamas J. R., Albar J. P., Marina A., Lópaz de Castro J. A. HLA-B27 (B*2701) specificity for peptides lacking Arg2 is determined by polymorphism outside the B pocket. Tissue Antigens. 1997 Jun;49(6):580–587. doi: 10.1111/j.1399-0039.1997.tb02805.x. [DOI] [PubMed] [Google Scholar]
  15. García F., Marina A., López de Castro J. A. Lack of carboxyl-terminal tyrosine distinguishes the B*2706-bound peptide repertoire from those of B*2704 and other HLA-B27 subtypes associated with ankylosing spondylitis. Tissue Antigens. 1997 Mar;49(3 Pt 1):215–221. doi: 10.1111/j.1399-0039.1997.tb02741.x. [DOI] [PubMed] [Google Scholar]
  16. García F., Rognan D., Lamas J. R., Marina A., López de Castro J. A. An HLA-B27 polymorphism (B*2710) that is critical for T-cell recognition has limited effects on peptide specificity. Tissue Antigens. 1998 Jan;51(1):1–9. doi: 10.1111/j.1399-0039.1998.tb02941.x. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Gonzalez-Roces S., Alvarez M. V., Gonzalez S., Dieye A., Makni H., Woodfield D. G., Housan L., Konenkov V., Abbadi M. C., Grunnet N. HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis. Tissue Antigens. 1997 Feb;49(2):116–123. doi: 10.1111/j.1399-0039.1997.tb02724.x. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Hermann E., Yu D. T., Meyer zum Büschenfelde K. H., Fleischer B. HLA-B27-restricted CD8 T cells derived from synovial fluids of patients with reactive arthritis and ankylosing spondylitis. Lancet. 1993 Sep 11;342(8872):646–650. doi: 10.1016/0140-6736(93)91760-j. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Kingsley G., Sieper J. Current perspectives in reactive arthritis. Immunol Today. 1993 Aug;14(8):387–391. doi: 10.1016/0167-5699(93)90139-C. [DOI] [PubMed] [Google Scholar]
  23. Krebs S., Lamas J. R., Poenaru S., Folkers G., de Castro J. A., Seebach D., Rognan D. Substituting nonpeptidic spacers for the T cell receptor-binding part of class I major histocompatibility complex-binding peptides. J Biol Chem. 1998 Jul 24;273(30):19072–19079. doi: 10.1074/jbc.273.30.19072. [DOI] [PubMed] [Google Scholar]
  24. Kunkel T. A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc Natl Acad Sci U S A. 1985 Jan;82(2):488–492. doi: 10.1073/pnas.82.2.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. López de Castro J. A. The pathogenetic role of HLA-B27 in chronic arthritis. Curr Opin Immunol. 1998 Feb;10(1):59–66. doi: 10.1016/s0952-7915(98)80033-2. [DOI] [PubMed] [Google Scholar]
  26. López-Larrea C., Sujirachato K., Mehra N. K., Chiewsilp P., Isarangkura D., Kanga U., Dominguez O., Coto E., Penã M., Setién F. HLA-B27 subtypes in Asian patients with ankylosing spondylitis. Evidence for new associations. Tissue Antigens. 1995 Mar;45(3):169–176. doi: 10.1111/j.1399-0039.1995.tb02436.x. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Madden D. R. The three-dimensional structure of peptide-MHC complexes. Annu Rev Immunol. 1995;13:587–622. doi: 10.1146/annurev.iy.13.040195.003103. [DOI] [PubMed] [Google Scholar]
  29. Merritt E. A., Murphy M. E. Raster3D Version 2.0. A program for photorealistic molecular graphics. Acta Crystallogr D Biol Crystallogr. 1994 Nov 1;50(Pt 6):869–873. doi: 10.1107/S0907444994006396. [DOI] [PubMed] [Google Scholar]
  30. Nasution A. R., Mardjuadi A., Kunmartini S., Suryadhana N. G., Setyohadi B., Sudarsono D., Lardy N. M., Feltkamp T. E. HLA-B27 subtypes positively and negatively associated with spondyloarthropathy. J Rheumatol. 1997 Jun;24(6):1111–1114. [PubMed] [Google Scholar]
  31. Parker K. C., Biddison W. E., Coligan J. E. Pocket mutations of HLA-B27 show that anchor residues act cumulatively to stabilize peptide binding. Biochemistry. 1994 Jun 21;33(24):7736–7743. doi: 10.1021/bi00190a029. [DOI] [PubMed] [Google Scholar]
  32. Raghavan M., Lebrón J. A., Johnson J. L., Bjorkman P. J. Extended repertoire of permissible peptide ligands for HLA-B*2702. Protein Sci. 1996 Oct;5(10):2080–2088. doi: 10.1002/pro.5560051014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ren E. C., Koh W. H., Sim D., Boey M. L., Wee G. B., Chan S. H. Possible protective role of HLA-B*2706 for ankylosing spondylitis. Tissue Antigens. 1997 Jan;49(1):67–69. doi: 10.1111/j.1399-0039.1997.tb02713.x. [DOI] [PubMed] [Google Scholar]
  34. Rognan D., Krebs S., Kuonen O., Lamas J. R., López de Castro J. A., Folkers G. Fine specificity of antigen binding to two class I major histocompatibility proteins (B*2705 and B*2703) differing in a single amino acid residue. J Comput Aided Mol Des. 1997 Sep;11(5):463–478. doi: 10.1023/a:1007963901092. [DOI] [PubMed] [Google Scholar]
  35. Rojo S., García F., Villadangos J. A., López de Castro J. A. Changes in the repertoire of peptides bound to HLA-B27 subtypes and to site-specific mutants inside and outside pocket B. J Exp Med. 1993 Mar 1;177(3):613–620. doi: 10.1084/jem.177.3.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rovero P., Riganelli D., Fruci D., Viganò S., Pegoŕaro S., Revoltella R., Greco G., Butler R., Clementi S., Tanigaki N. The importance of secondary anchor residue motifs of HLA class I proteins: a chemometric approach. Mol Immunol. 1994 May;31(7):549–554. doi: 10.1016/0161-5890(94)90042-6. [DOI] [PubMed] [Google Scholar]
  37. Rötzschke O., Falk K., Stevanović S., Gnau V., Jung G., Rammensee H. G. Dominant aromatic/aliphatic C-terminal anchor in HLA-B*2702 and B*2705 peptide motifs. Immunogenetics. 1994;39(1):74–77. doi: 10.1007/BF00171803. [DOI] [PubMed] [Google Scholar]
  38. Saper M. A., Bjorkman P. J., Wiley D. C. Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 A resolution. J Mol Biol. 1991 May 20;219(2):277–319. doi: 10.1016/0022-2836(91)90567-p. [DOI] [PubMed] [Google Scholar]
  39. Simmons W. A., Summerfield S. G., Roopenian D. C., Slaughter C. A., Zuberi A. R., Gaskell S. J., Bordoli R. S., Hoyes J., Moomaw C. R., Colbert R. A. Novel HY peptide antigens presented by HLA-B27. J Immunol. 1997 Sep 15;159(6):2750–2759. [PubMed] [Google Scholar]
  40. Smith K. J., Reid S. W., Harlos K., McMichael A. J., Stuart D. I., Bell J. I., Jones E. Y. Bound water structure and polymorphic amino acids act together to allow the binding of different peptides to MHC class I HLA-B53. Immunity. 1996 Mar;4(3):215–228. doi: 10.1016/s1074-7613(00)80430-6. [DOI] [PubMed] [Google Scholar]
  41. Smith K. J., Reid S. W., Stuart D. I., McMichael A. J., Jones E. Y., Bell J. I. An altered position of the alpha 2 helix of MHC class I is revealed by the crystal structure of HLA-B*3501. Immunity. 1996 Mar;4(3):203–213. doi: 10.1016/s1074-7613(00)80429-x. [DOI] [PubMed] [Google Scholar]
  42. Tieng V., Dulphy N., Boisgérault F., Tamouza R., Charron D., Toubert A. HLA-B*2707 peptide motif: Tyr C-terminal anchor is not shared by all disease-associated subtypes. Immunogenetics. 1997;47(1):103–105. doi: 10.1007/s002510050334. [DOI] [PubMed] [Google Scholar]
  43. Ugrinovic S., Mertz A., Wu P., Braun J., Sieper J. A single nonamer from the Yersinia 60-kDa heat shock protein is the target of HLA-B27-restricted CTL response in Yersinia-induced reactive arthritis. J Immunol. 1997 Dec 1;159(11):5715–5723. [PubMed] [Google Scholar]
  44. 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]
  45. Zhou M., Sayad A., Simmons W. A., Jones R. C., Maika S. D., Satumtira N., Dorris M. L., Gaskell S. J., Bordoli R. S., Sartor R. B. The specificity of peptides bound to human histocompatibility leukocyte antigen (HLA)-B27 influences the prevalence of arthritis in HLA-B27 transgenic rats. J Exp Med. 1998 Sep 7;188(5):877–886. doi: 10.1084/jem.188.5.877. [DOI] [PMC free article] [PubMed] [Google Scholar] [Research Misconduct Found]

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