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Immunogenetics

, Volume 65, Issue 3, pp 157–172 | Cite as

Dynamics of free versus complexed β2-microglobulin and the evolution of interfaces in MHC class I molecules

  • Chee-Seng Hee
  • Monika Beerbaum
  • Bernhard Loll
  • Martin Ballaschk
  • Peter Schmieder
  • Barbara Uchanska-Ziegler
  • Andreas Ziegler
Original Paper

Abstract

In major histocompatibility complex (MHC) class I molecules, monomorphic β2-microglobulin (β2m) is non-covalently bound to a heavy chain (HC) exhibiting a variable degree of polymorphism. β2M can stabilize a wide variety of complexes ranging from classical peptide binding to nonclassical lipid presenting MHC class I molecules as well as to MHC class I-like molecules that do not bind small ligands. Here we aim to assess the dynamics of individual regions in free as well as complexed β2m and to understand the evolution of the interfaces between β2m and different HC. Using human β2m and the HLA–B*27:09 complex as a model system, a comparison of free and HC-bound β2m by nuclear magnetic resonance spectroscopy was initially carried out. Although some regions retain their flexibility also after complex formation, these studies reveal that most parts of β2m gain rigidity upon binding to the HC. Sequence analyses demonstrate that some of the residues exhibiting flexibility participate in evolutionarily conserved β2m–HC contacts which are detectable in diverse vertebrate species or characterize a particular group of MHC class I complexes such as peptide- or lipid-binding molecules. Therefore, the spectroscopic experiments and the interface analyses demonstrate that β2m fulfills its role of interacting with diverse MHC class I HC as well as effector cell receptors not only by engaging in conserved intermolecular contacts but also by falling back upon key interface residues that exhibit a high degree of flexibility.

Keywords

β2m dynamics β2m–MHC class I heavy chain interface MHC class I and class I-like molecules MHC evolution NMR spectroscopy 

Notes

Acknowledgments

We are grateful to Christina Schnick (Institut für Immungenetik, Charité-Universitätsmedizin Berlin), Annette Diehl and Natalja Erdmann (Leibniz-Institut für Molekulare Pharmakologie, Berlin) for excellent technical support. This work was supported by the Deutsche Forschungsgemeinschaft (grants Na226/12-3, UC8/1-2, UC8/2-1, SCHM880/9-1 and SFB 449/B6). A. Ziegler thanks the VolkswagenStiftung for financial assistance (grant I/79 989). B. Loll is grateful for support by the Forschungskommission of the Freie Universität Berlin and Fonds der Chemischen Industrie. C.-S. Hee thanks the Berliner Krebsgesellschaft (Ernst von Leyden Stipendium) and the Deutsche Forschungsgemeinschaft for support through UC8/2-1.

Supplementary material

251_2012_667_Fig5_ESM.jpg (194 kb)
Fig. S1

Amino acid sequence alignment of MHC class I and class I-like HC. Only positions involved in contacting β2m are shown, see Table 2 for the interactions and accession numbers in “Materials and methods” for the amino acid sequences used in this alignment (JPEG 194 kb)

251_2012_667_MOESM1_ESM.tif (1018 kb)
High resolution image (TIFF 1017 kb)
251_2012_667_Fig6_ESM.jpg (62 kb)
Fig. S2

Evolutionary relationship of MHC class I and class I-like HC from various species. The phylogenetic tree was generated from the sequence alignment of the α1-α2-α3 domains (approximately residues 1–270). Branches corresponding to partitions reproduced in less than 50 % bootstrap replicates are collapsed. The percentages of replicate trees in which the associated taxa clustered in the bootstrap test (1,000 replicates) are shown above the branches (JPEG 62 kb)

251_2012_667_MOESM2_ESM.tif (646 kb)
High resolution image (TIFF 645 kb)

References

  1. Achour A, Michaelsson J, Harris RA, Ljunggren HG, Karre K, Schneider G, Sandalova T (2006) Structural basis of the differential stability and receptor specificity of H-2Db in complex with murine versus human beta2-microglobulin. J Mol Biol 356:382–396PubMedCrossRefGoogle Scholar
  2. Armstrong KM, Piepenbrink KH, Baker BM (2008) Conformational changes and flexibility in T-cell receptor recognition of peptide-MHC complexes. Biochem J 415:183–196PubMedCrossRefGoogle Scholar
  3. Becker JW, Reeke GN Jr (1985) Three-dimensional structure of beta 2-microglobulin. Proc Natl Acad Sci USA 82:4225–4229PubMedCrossRefGoogle Scholar
  4. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC (1987) Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329:506–512PubMedCrossRefGoogle Scholar
  5. Boyington JC, Brooks AG, Sun PD (2001) Structure of killer cell immunoglobulin-like receptors and their recognition of the class I MHC molecules. Immunol Rev 181:66–78PubMedCrossRefGoogle Scholar
  6. Cavanagh J, Fairbrother JW, Palmer AG III, Skelton NJ (1996) Protein NMR spectroscopy principles and practice. Academic Press, San DiegoGoogle Scholar
  7. Chen Y, Shi Y, Cheng H, An YQ, Gao GF (2009) Structural immunology and crystallography help immunologists see the immune system in action: how T and NK cells touch their ligands. IUBMB Life 61:579–590PubMedCrossRefGoogle Scholar
  8. Chen W, Gao F, Chu F, Zhang J, Gao GF, Xia C (2010) Crystal structure of a bony fish beta2-microglobulin: insights into the evolutionary origin of immunoglobulin superfamily constant molecules. J Biol Chem 285:22505–22512PubMedCrossRefGoogle Scholar
  9. Chu F, Lou Z, Chen YW, Liu Y, Gao B, Zong L, Khan AH, Bell JI, Rao Z, Gao GF (2007) First glimpse of the peptide presentation by rhesus macaque MHC class I: crystal structures of Mamu-A*01 complexed with two immunogenic SIV epitopes and insights into CTL escape. J Immunol 178:944–952PubMedGoogle Scholar
  10. Clements CS, Kjer-Nielsen L, Kostenko L, Hoare HL, Dunstone MA, Moses E, Freed K, Brooks AG, Rossjohn J, McCluskey J (2005) Crystal structure of HLA-G: a nonclassical MHC class I molecule expressed at the fetal-maternal interface. Proc Natl Acad Sci USA 102:3360–3365PubMedCrossRefGoogle Scholar
  11. Collaborative Computational Project N4 (1994) The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr 50:760–763CrossRefGoogle Scholar
  12. Dam J, Guan R, Natarajan K, Dimasi N, Chlewicki LK, Kranz DM, Schuck P, Margulies DH, Mariuzza RA (2003) Variable MHC class I engagement by Ly49 natural killer cell receptors demonstrated by the crystal structure of Ly49C bound to H-2 K(b). Nat Immunol 4:1213–1222PubMedCrossRefGoogle Scholar
  13. Delano WL (2002) The PyMOL Molecular Graphic System. San Carlos, CA, DeLano ScientificGoogle Scholar
  14. Deng L, Cho S, Malchiodi EL, Kerzic MC, Dam J, Mariuzza RA (2008) Molecular architecture of the major histocompatibility complex class I-binding site of Ly49 natural killer cell receptors. J Biol Chem 283:16840–16849PubMedCrossRefGoogle Scholar
  15. R Development Core Team (2010) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. http://www.r-project.org/
  16. Dvir H, Wang J, Ly N, Dascher CC, Zajonc DM (2010) Structural basis for lipid-antigen recognition in avian immunity. J Immunol 184:2504–2511PubMedCrossRefGoogle Scholar
  17. Eichner T, Kalverda AP, Thompson GS, Homans SW, Radford SE (2011) Conformational conversion during amyloid formation at atomic resolution. Mol Cell 41:161–172PubMedCrossRefGoogle Scholar
  18. Esposito G, Corazza A, Viglino P, Verdone G, Pettirossi F, Fogolari F, Makek A, Giorgetti S, Mangione P, Stoppini M, Bellotti V (2005) Solution structure of beta(2)-microglobulin and insights into fibrillogenesis. Biochim Biophys Acta 1753:76–84PubMedCrossRefGoogle Scholar
  19. Esposito G, Ricagno S, Corazza A, Rennella E, Gümral D, Mimmi MC, Betto E, Pucillo CE, Fogolari F, Viglino P, Raimondi S, Giorgetti S, Bolognesi B, Merlini G, Stoppini M, Bolognesi M, Bellotti V (2008) The controlling roles of Trp60 and Trp95 in beta2-microglobulin function, folding and amyloid aggregation properties. J Mol Biol 378:887–897PubMedCrossRefGoogle Scholar
  20. Fabian H, Huser H, Narzi D, Misselwitz R, Loll B, Ziegler A, Böckmann RA, Uchanska-Ziegler B, Naumann D (2008) HLA-B27 subtypes differentially associated with disease exhibit conformational differences in solution. J Mol Biol 376:798–810PubMedCrossRefGoogle Scholar
  21. Fabian H, Huser H, Loll B, Ziegler A, Naumann D, Uchanska-Ziegler B (2010) HLA-B27 heavy chains distinguished by a micropolymorphism exhibit differential flexibility. Arthritis Rheum 62:978–987PubMedCrossRefGoogle Scholar
  22. Fabian H, Loll B, Huser H, Naumann D, Uchanska-Ziegler B, Ziegler A (2011) Influence of inflammation-related changes on conformational characteristics of HLA-B27 subtypes as detected by IR spectroscopy. FEBS J 278:1713–1727PubMedCrossRefGoogle Scholar
  23. Fan QR, Wiley DC (1999) Structure of human histocompatibility leukocyte antigen (HLA)-Cw4, a ligand for the KIR2D natural killer cell inhibitory receptor. J Exp Med 190:113–123PubMedCrossRefGoogle Scholar
  24. Farrow NA, Zhang O, Forman-Kay JD, Kay LE (1994) A heteronuclear correlation experiment for simultaneous determination of 15 N longitudinal decay and chemical exchange rates of systems in slow equilibrium. J Biomol NMR 4:727–734PubMedCrossRefGoogle Scholar
  25. Gao GF, Tormo J, Gerth UC, Wyer JR, McMichael AJ, Stuart DI, Bell JI, Jones EY, Jakobsen BK (1997) Crystal structure of the complex between human CD8alpha(alpha) and HLA-A2. Nature 387:630–634PubMedCrossRefGoogle Scholar
  26. Gouet P, Courcelle E, Stuart DI, Metoz F (1999) ESPript: analysis of multiple sequence alignments in PostScript. Bioinformatics 15:305–308PubMedCrossRefGoogle Scholar
  27. Gras S, Kjer-Nielsen L, Chen Z, Rossjohn J, McCluskey J (2011) The structural bases of direct T-cell allorecognition: implications for T-cell-mediated transplant rejection. Immunol Cell Biol 89:388–395PubMedCrossRefGoogle Scholar
  28. Hassan MI, Ahmad F (2011) Structural diversity of class I MHC-like molecules and its implications in binding specificities. Adv Protein Chem Struct Biol 83:223–270PubMedCrossRefGoogle Scholar
  29. Hassan MI, Bilgrami S, Kumar V, Singh N, Yadav S, Kaur P, Singh TP (2008) Crystal structure of the novel complex formed between zinc alpha2-glycoprotein (ZAG) and prolactin-inducible protein (PIP) from human seminal plasma. J Mol Biol 384:663–672PubMedCrossRefGoogle Scholar
  30. Hawse WF, Champion MM, Joyce MV, Hellman LM, Hossain M, Ryan V, Pierce BG, Weng Z, Baker BM (2012) Cutting edge: Evidence for a dynamically driven T cell signalling mechanism. J Immunol 188:5819–5823PubMedCrossRefGoogle Scholar
  31. Hee CS, Gao S, Loll B, Miller MM, Uchanska-Ziegler B, Daumke O, Ziegler A (2010) Structure of a classical MHC class I molecule that binds "non-classical" ligands. PLoS Biol 8:e1000557PubMedCrossRefGoogle Scholar
  32. Hee CS, Fabian H, Uchanska-Ziegler B, Ziegler A, Loll B (2012) Comparative biophysical characterization of chicken β2-microglobulin. Biophys Chem 167:26–35PubMedCrossRefGoogle Scholar
  33. Henzler-Wildman K, Kern D (2007) Dynamic personalities of proteins. Nature 450:964–972PubMedCrossRefGoogle Scholar
  34. Holmes MA, Li P, Petersdorf EW, Strong RK (2002) Structural studies of allelic diversity of the MHC class I homolog MIC-B, a stress-inducible ligand for the activating immunoreceptor NKG2D. J Immunol 169:1395–1400PubMedGoogle Scholar
  35. Hülsmeyer M, Hillig RC, Volz A, Rühl M, Schröder W, Saenger W, Ziegler A, Uchanska-Ziegler B (2002) HLA-B27 subtypes differentially associated with disease exhibit subtle structural alterations. J Biol Chem 277:47844–47853PubMedCrossRefGoogle Scholar
  36. Hülsmeyer M, Fiorillo MT, Bettosini F, Sorrentino R, Saenger W, Ziegler A, Uchanska-Zlegler B (2004) Dual HLA-B27 subtype-dependent conformation of a self-peptide. J Exp Med 199:271–281PubMedCrossRefGoogle Scholar
  37. Iwata K, Matsuura T, Sakurai K, Nakagawa A, Goto Y (2007) High-resolution crystal structure of beta2-microglobulin formed at pH 7.0. J Biochem 142:413–419PubMedCrossRefGoogle Scholar
  38. Jiang N, Edwards LJ, Liu B, Zhang Y, Beal CD, Evavold BD, Zhu C (2011) Two-stage cooperative T cell receptor-peptide major histocompatibility complex-CD8 trimolecular interactions amplify antigen discrimination. Immunity 34:13–23PubMedCrossRefGoogle Scholar
  39. Kern PS, Teng MK, Smolyar A, Liu JH, Liu J, Hussey RE, Spoerl R, Chang HC, Reinherz EL, Wang JH (1998) Structural basis of CD8 coreceptor function revealed by crystallographic analysis of a murine CD8alphaalpha ectodomain fragment in complex with H-2Kb. Immunity 9:519–530PubMedCrossRefGoogle Scholar
  40. Koch M, Camp S, Collen T, Avila D, Salomonsen J, Wallny HJ, van Hateren A, Hunt L, Jacob JP, Johnston F, Marston DA, Shaw I, Dunbar PR, Cerundolo V, Jones EY, Kaufman J (2007) Structures of an MHC class I molecule from B21 chickens illustrate promiscuous peptide binding. Immunity 27:885–899PubMedCrossRefGoogle Scholar
  41. Li P, Willie ST, Bauer S, Morris DL, Spies T, Strong RK (1999) Crystal structure of the MHC class I homolog MIC-A, a gammadelta T cell ligand. Immunity 10:577–584PubMedCrossRefGoogle Scholar
  42. Li X, Liu J, Qi J, Gao F, Li Q, Li X, Zhang N, Xia C, Gao GF (2011) Two distinct conformations of a rinderpest virus epitope presented by bovine major histocompatibility complex class I n*01801: a host strategy to present featured peptides. J Virol 85:6038–6048PubMedCrossRefGoogle Scholar
  43. Liu Y, Xiong Y, Naidenko OV, Liu JH, Zhang R, Joachimiak A, Kronenberg M, Cheroutre H, Reinherz EL, Wang JH (2003) The crystal structure of a TL/CD8alphaalpha complex at 2.1 Å resolution: implications for modulation of T cell activation and memory. Immunity 18:205–215PubMedCrossRefGoogle Scholar
  44. Madden DR, Garboczi DN, Wiley DC (1993) The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2. Cell 75:693–708PubMedCrossRefGoogle Scholar
  45. Maenaka K, Jones EY (1999) MHC superfamily structure and the immune system. Curr Opin Struct Biol 9:745–753PubMedCrossRefGoogle Scholar
  46. McParland VJ, Kalverda AP, Homans SW, Radford SE (2002) Structural properties of an amyloid precursor of beta(2)-microglobulin. Nat Struct Biol 9:326–331PubMedCrossRefGoogle Scholar
  47. Morin S (2011) A practical guide to protein dynamics from 15 N spin relaxation in solution. Prog Nucl Magn Reson 59:245–262CrossRefGoogle Scholar
  48. Narzi D, Becker CM, Fiorillo MT, Uchanska-Ziegler B, Ziegler A, Böckmann RA (2012) Dynamical characterization of two differentially disease associated MHC class I proteins in complex with viral and self-peptides. J Mol Biol 415:429–442PubMedCrossRefGoogle Scholar
  49. O'Callaghan CA, Tormo J, Willcox BE, Braud VM, Jakobsen BK, Stuart DI, McMichael AJ, Bell JI, Jones EY (1998) Structural features impose tight peptide binding specificity in the nonclassical MHC molecule HLA-E. Mol Cell 1:531–541PubMedCrossRefGoogle Scholar
  50. Okon M, Bray P, Vucelić D (1992) 1H NMR assignments and secondary structure of human beta 2-microglobulin in solution. Biochemistry 31:8906-8915.Google Scholar
  51. Palmer AG III (2004) NMR characterization of the dynamics of biomacromolecules. Chem Rev 104:3623–3640PubMedCrossRefGoogle Scholar
  52. Pedersen LO, Hansen AS, Olsen AC, Gerwien J, Nissen MH, Buus S (1994) The interaction between beta 2-microglobulin (beta 2 m) and purified class-I major histocompatibility (MHC) antigen. Scand J Immunol 39:64–72PubMedCrossRefGoogle Scholar
  53. Pervushin K, Riek R, Wider G, Wüthrich K (1997) Attenuated T2 relaxation by mutual cancellation of dipole-dipole coupling and chemical shift anisotropy indicates an avenue to NMR structures of very large biological macromolecules in solution. Proc Natl Acad Sci USA 94:12366–12371PubMedCrossRefGoogle Scholar
  54. Platt GW, McParland VJ, Kalverda AP, Homans SW, Radford SE (2005) Dynamics in the unfolded state of beta2-microglobulin studied by NMR. J Mol Biol 346:279–294PubMedCrossRefGoogle Scholar
  55. Rudolph MG, Stanfield RL, Wilson IA (2006) How TCRs bind MHCs, peptides, and coreceptors. Annu Rev Immunol 24:419–466PubMedCrossRefGoogle Scholar
  56. Sanchez LM, Chirino AJ, Bjorkman P (1999) Crystal structure of human ZAG, a fat-depleting factor related to MHC molecules. Science 283:1914–1919PubMedCrossRefGoogle Scholar
  57. Shi Y, Qi J, Iwamoto A, Gao GF (2011) Plasticity of human CD8alphaalpha binding to peptide-HLA-A*2402. Mol Immunol 48:2198–2202PubMedCrossRefGoogle Scholar
  58. Shields MJ, Kubota R, Hodgson W, Jacobson S, Biddison WE, Ribaudo RK (1998) The effect of human beta2-microglobulin on major histocompatibility complex I peptide loading and the engineering of a high affinity variant. Implications for peptide-based vaccines. J Biol Chem 273:28010–28018PubMedCrossRefGoogle Scholar
  59. Shiroishi M, Kuroki K, Rasubala L, Tsumoto K, Kumagai I, Kurimoto E, Kato K, Kohda D, Maenaka K (2006) Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d). Proc Natl Acad Sci USA 103:16412–16417PubMedCrossRefGoogle Scholar
  60. Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680PubMedCrossRefGoogle Scholar
  61. Tormo J, Natarajan K, Margulies DH, Mariuzza RA (1999) Crystal structure of a lectin-like natural killer cell receptor bound to its MHC class I ligand. Nature 402:623–631PubMedCrossRefGoogle Scholar
  62. Trinh CH, Smith DP, Kalverda AP, Phillips SEV, Radford SE (2002) Crystal structure of monomeric human beta-2-microglobulin reveals clues to its amyloidogenic properties. Proc Natl Acad Sci USA 99:9771–9776PubMedCrossRefGoogle Scholar
  63. Tugarinov V, Hwang PM, Kay LE (2004) Nuclear magnetic resonance spectroscopy of high-molecular-weight proteins. Annu Rev Biochem 73:107–146PubMedCrossRefGoogle Scholar
  64. Verdone G, Corazza A, Viglino P, Pettirossi F, Giorgetti S, Mangione P, Andreola A, Stoppini M, Bellotti V, Esposito G (2002) The solution structure of human beta2-microglobulin reveals the prodromes of its amyloid transition. Prot Sci 11:487–499CrossRefGoogle Scholar
  65. Vranken WF, Boucher W, Stevens TJ, Fogh RH, Pajon A, Llinas M, Ulrich EL, Markley JL, Ionides J, Laue ED (2005) The CCPN data model for NMR spectroscopy: development of a software pipeline. Proteins 59:687–696PubMedCrossRefGoogle Scholar
  66. Wang R, Natarajan K, Margulies DH (2009) Structural basis of the CD8 alpha beta/MHC class I interaction: focused recognition orients CD8 beta to a T cell proximal position. J Immunol 183:2554–2564PubMedCrossRefGoogle Scholar
  67. Willcox BE, Thomas LM, Bjorkman PJ (2003) Crystal structure of HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex receptor. Nat Immunol 4:913–91PubMedCrossRefGoogle Scholar
  68. Zajonc DM, Elsliger MA, Teyton L, Wilson IA (2003) Crystal structure of CD1a in complex with a sulfatide self antigen at a resolution of 2.15 A. Nat Immunol 4:808–815PubMedCrossRefGoogle Scholar
  69. Zajonc DM, Striegl H, Dascher CC, Wilson IA (2008) The crystal structure of avian CD1 reveals a smaller, more primordial antigen-binding pocket compared to mammalian CD1. Proc Natl Acad Sci USA 105:17925–17930PubMedCrossRefGoogle Scholar
  70. Zeng ZH, Castano AR, Segelke BW, Stura EA, Peterson PA, Wilson IA (1997) Crystal structure of mouse CD1: An MHC-like fold with a large hydrophobic binding groove. Science 277:339–345PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Chee-Seng Hee
    • 1
    • 4
  • Monika Beerbaum
    • 2
  • Bernhard Loll
    • 3
  • Martin Ballaschk
    • 2
  • Peter Schmieder
    • 2
  • Barbara Uchanska-Ziegler
    • 1
  • Andreas Ziegler
    • 1
  1. 1.Institut für Immungenetik, Charité - Universitätsmedizin BerlinFreie Universität BerlinBerlinGermany
  2. 2.Leibniz-Institut für Molekulare PharmakologieBerlinGermany
  3. 3.Institut für Chemie und Biochemie, Abteilung StrukturbiochemieFreie Universität BerlinBerlinGermany
  4. 4.BiozentrumUniversität BaselBaselSwitzerland

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