A Conserved Host and Pathogen Recognition Site on Immunoglobulins: Structural and Functional Aspects

  • Bruce D. Wines
  • Halina M. Trist
  • William Farrugia
  • Chloe Ngo
  • John Trowsdale
  • Thomas Areschoug
  • Gunnar Lindahl
  • John D. Fraser
  • Paul A. RamslandEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 946)


A common site in the constant region (Fc) of immunoglobulins is recognized by host receptors and is a frequent target of proteins expressed by pathogens. This site is located at the junction of two constant domains in the antibody heavy chains and produces a large shallow cavity formed by loops of the CH2 and CH3 domains in IgG and IgA (CH3 and CH4 domains in IgM). Crystal structures have been determined for complexes of IgG-Fc and IgA-Fc with a structurally diverse set of host, pathogen and in vitro selected ligands. While pathogen proteins may directly block interactions with the immunoglobulins thereby evading host immunity, it is likely that the same pathogen molecules also interact with other host factors to carry out their primary biological function. Herein we review the structural and functional aspects of host and pathogen molecular recognition of the common site on the Fc of immunoglobulins. We also propose that some pathogen proteins may promote virulence by affecting the bridging between innate and adaptive immunity.


Pathogen Host Antibody Complement Bacteria Carbohydrate Crystal structure Domain junction 



This work was funded by grant ID543317 (to PAR and BDW) from the National Health and Medical Research Council of Australia (NHMRC). PAR was a recipient of an RD Wright CDA (ID365209) from the NHMRC. JT was supported by the MRC and the Wellcome Trust with partial support from the NIHR Cambridge Biomedical Research Centre. The authors gratefully acknowledge the contribution to this work of the Victorian Operational Infrastructure Support Program received by the Burnet Institute.


  1. Akerstrom, B., Nielsen, E. and Bjorck, L. (1987) Definition of IgG- and albumin-binding regions of streptococcal protein G. J Biol Chem 262, 13388-13391PubMedGoogle Scholar
  2. Apostolopoulos, V., Yuriev, E., Lazoura, E., Yu, M. and Ramsland, P.A. (2008) MHC and MHC-like molecules: structural perspectives on the design of molecular vaccines. Hum Vaccin 4, 400-409PubMedGoogle Scholar
  3. Areschoug, T., Stalhammar-Carlemalm, M., Karlsson, I. and Lindahl, G. (2002) Streptococcal beta protein has separate binding sites for human factor H and IgA-Fc. J Biol Chem 277, 12642-12648PubMedGoogle Scholar
  4. Arnold, J.N., Wormald, M.R., Suter, D.M., Radcliffe, C.M., Harvey, D.J., Dwek, R.A., Rudd, P.M. and Sim, R.B. (2005) Human serum IgM glycosylation: identification of glycoforms that can bind to mannan-binding lectin. J Biol Chem 280, 29080-29087PubMedGoogle Scholar
  5. Artandi, S.E., Calame, K.L., Morrison, S.L. and Bonagura, V.R. (1992) Monoclonal IgM rheumatoid factors bind IgG at a discontinuous epitope comprised of amino acid loops from heavy-chain constant-region domains 2 and 3. Proc Natl Acad Sci U S A 89, 94-98PubMedGoogle Scholar
  6. Baucke, R.B. and Spear, P.G. (1979) Membrane proteins specified by herpes simplex viruses. V. Identification of an Fc-binding glycoprotein. J Virol 32, 779-789PubMedGoogle Scholar
  7. Bestebroer, J., Aerts, P.C., Rooijakkers, S.H., Pandey, M.K., Kohl, J., van Strijp, J.A. and de Haas, C.J. (2010) Functional basis for complement evasion by staphylococcal superantigen-like 7. Cell Microbiol 12, 1506-1516PubMedGoogle Scholar
  8. Boehm, M.K., Woof, J.M., Kerr, M.A. and Perkins, S.J. (1999) The Fab and Fc fragments of IgA1 exhibit a different arrangement from that in IgG: a study by X-ray and neutron solution scattering and homology modelling. J Mol Biol 286, 1421-1447PubMedGoogle Scholar
  9. Bolland, S. and Garcia-Sastre, A. (2009) Vicious circle: systemic autoreactivity in Ro52/TRIM21-deficient mice. J Exp Med 206, 1647-1651PubMedGoogle Scholar
  10. Bonagura, V.R., Agostino, N., Borretzen, M., Thompson, K.M., Natvig, J.B. and Morrison, S.L. (1998) Mapping IgG epitopes bound by rheumatoid factors from immunized controls identifies disease-specific rheumatoid factors produced by patients with rheumatoid arthritis. J Immunol 160, 2496-2505PubMedGoogle Scholar
  11. Bonner, A., Almogren, A., Furtado, P.B., Kerr, M.A. and Perkins, S.J. (2009) Location of secretory component on the Fc edge of dimeric IgA1 reveals insight into the role of secretory IgA1 in mucosal immunity. Mucosal Immunol 2, 74-84PubMedGoogle Scholar
  12. Bonner, A., Furtado, P.B., Almogren, A., Kerr, M.A. and Perkins, S.J. (2008) Implications of the near-planar solution structure of human myeloma dimeric IgA1 for mucosal immunity and IgA nephropathy. J Immunol 180, 1008-1018PubMedGoogle Scholar
  13. Burmeister, W.P., Huber, A.H. and Bjorkman, P.J. (1994) Crystal structure of the complex of rat neonatal Fc receptor with Fc. Nature 372, 379-383PubMedGoogle Scholar
  14. Carayannopoulos, L., Hexham, J.M. and Capra, J.D. (1996) Localization of the binding site for the monocyte immunoglobulin (Ig) A-Fc receptor (CD89) to the domain boundary between Calpha2 and Calpha3 in human IgA1. J Exp Med 183, 1579-1586PubMedGoogle Scholar
  15. Carlin, A.F., Chang, Y.C., Areschoug, T., Lindahl, G., Hurtado-Ziola, N., King, C.C., Varki, A. and Nizet, V. (2009) Group B Streptococcus suppression of phagocyte functions by protein-mediated engagement of human Siglec-5. J Exp Med 206, 1691-1699PubMedGoogle Scholar
  16. Carlsson, F., Berggard, K., Stalhammar-Carlemalm, M. and Lindahl, G. (2003) Evasion of phagocytosis through cooperation between two ligand-binding regions in Streptococcus pyogenes M protein. J Exp Med 198, 1057-1068PubMedGoogle Scholar
  17. Corper, A.L., Sohi, M.K., Bonagura, V.R., Steinitz, M., Jefferis, R., Feinstein, A., Beale, D., Taussig, M.J. and Sutton, B.J. (1997) Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a novel topology of antibody-antigen interaction. Nat Struct Biol 4, 374-381PubMedGoogle Scholar
  18. Czajkowsky, D.M. and Shao, Z. (2009) The human IgM pentamer is a mushroom-shaped molecule with a flexural bias. Proc Natl Acad Sci U S A 106, 14960-14965PubMedGoogle Scholar
  19. Czajkowsky, D.M., Salanti, A., Ditlev, S.B., Shao, Z., Ghumra, A., Rowe, J.A. and Pleass, R.J. (2010) IgM, Fc mu Rs, and malarial immune evasion. J Immunol 184, 4597-4603PubMedGoogle Scholar
  20. Dancer, S.J. (2008) The effect of antibiotics on methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother 61, 246-253PubMedGoogle Scholar
  21. Deisenhofer, J. (1981) Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A from Staphylococcus aureus at 2.9- and 2.8-A resolution. Biochemistry 20, 2361-2370Google Scholar
  22. DeLano, W.L., Ultsch, M.H., de Vos, A.M. and Wells, J.A. (2000) Convergent solutions to binding at a protein-protein interface. Science 287, 1279-1283PubMedGoogle Scholar
  23. Dubin, G., Socolof, E., Frank, I. and Friedman, H.M. (1991) Herpes simplex virus type 1 Fc receptor protects infected cells from antibody-dependent cellular cytotoxicity. J Virol 65, 7046-7050PubMedGoogle Scholar
  24. Duquerroy, S., Stura, E.A., Bressanelli, S., Fabiane, S.M., Vaney, M.C., Beale, D., Hamon, M., Casali, P., Rey, F.A., Sutton, B.J. and Taussig, M.J. (2007) Crystal structure of a human autoimmune complex between IgM rheumatoid factor RF61 and IgG1 Fc reveals a novel epitope and evidence for affinity maturation. J Mol Biol 368, 1321-1331PubMedGoogle Scholar
  25. Edmundson, A.B., Tribbick, G., Plompen, S., Geysen, H.M., Yuriev, E. and Ramsland, P.A. (2001) Binding of synthetic peptides by a human monoclonal IgM with an unusual combining site structure. J Mol Recognit 14, 229-238PubMedGoogle Scholar
  26. Espinosa, A., Dardalhon, V., Brauner, S., Ambrosi, A., Higgs, R., Quintana, F.J., Sjostrand, M., Eloranta, M.L., Ni Gabhann, J., Winqvist, O., Sundelin, B., Jefferies, C.A., Rozell, B., Kuchroo, V.K. and Wahren-Herlenius, M. (2009) Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway. J Exp Med 206, 1661-1671PubMedGoogle Scholar
  27. Frank, I. and Friedman, H.M. (1989) A novel function of the herpes simplex virus type 1 Fc receptor: participation in bipolar bridging of antiviral immunoglobulin G. J Virol 63, 4479-4488PubMedGoogle Scholar
  28. Frick, I.M., Wikstrom, M., Forsen, S., Drakenberg, T., Gomi, H., Sjobring, U. and Bjorck, L. (1992) Convergent evolution among immunoglobulin G-binding bacterial proteins. Proc Natl Acad Sci U S A 89, 8532-8536PubMedGoogle Scholar
  29. Furtado, P.B., Whitty, P.W., Robertson, A., Eaton, J.T., Almogren, A., Kerr, M.A., Woof, J.M. and Perkins, S.J. (2004) Solution structure determination of monomeric human IgA2 by X-ray and neutron scattering, analytical ultracentrifugation and constrained modelling: a comparison with monomeric human IgA1. J Mol Biol 338, 921-941PubMedGoogle Scholar
  30. Ghumra, A., Semblat, J.P., McIntosh, R.S., Raza, A., Rasmussen, I.B., Braathen, R., Johansen, F.E., Sandlie, I., Mongini, P.K., Rowe, J.A. and Pleass, R.J. (2008) Identification of residues in the Cmu4 domain of polymeric IgM essential for interaction with Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). J Immunol 181, 1988-2000PubMedGoogle Scholar
  31. Ghumra, A., Shi, J., McIntosh, R.S., Rasmussen, I.B., Braathen, R., Johansen, F.E., Sandlie, I., Mongini, P.K., Areschoug, T., Lindahl, G., Lewis, M.J., Woof, J.M. and Pleass, R.J. (2009) Structural requirements for the interaction of human IgM and IgA with the human Fcalpha/mu receptor. Eur J Immunol 39, 1147-1156PubMedGoogle Scholar
  32. Gomes, M.M. and Herr, A.B. (2006) IgA and IgA-specific receptors in human disease: structural and functional insights into pathogenesis and therapeutic potential. Springer Semin Immunopathol 28, 383-395PubMedGoogle Scholar
  33. Gomez, M.I., Lee, A., Reddy, B., Muir, A., Soong, G., Pitt, A., Cheung, A. and Prince, A. (2004) Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1. Nat Med 10, 842-848PubMedGoogle Scholar
  34. Goodyear, C.S., Corr, M., Sugiyama, F., Boyle, D.L. and Silverman, G.J. (2007) Cutting Edge: Bim is required for superantigen-mediated B cell death. J Immunol 178, 2636-2640PubMedGoogle Scholar
  35. Graille, M., Stura, E.A., Corper, A.L., Sutton, B.J., Taussig, M.J., Charbonnier, J.B. and Silverman, G.J. (2000) Crystal structure of a Staphylococcus aureus protein A domain complexed with the Fab fragment of a human IgM antibody: structural basis for recognition of B-cell receptors and superantigen activity. Proc Natl Acad Sci U S A 97, 5399-5404PubMedGoogle Scholar
  36. Guddat, L.W., Herron, J.N. and Edmundson, A.B. (1993) Three-dimensional structure of a human immunoglobulin with a hinge deletion. Proc Natl Acad Sci U S A 90, 4271-4275PubMedGoogle Scholar
  37. Hartleib, J., Kohler, N., Dickinson, R.B., Chhatwal, G.S., Sixma, J.J., Hartford, O.M., Foster, T.J., Peters, G., Kehrel, B.E. and Herrmann, M. (2000) Protein A is the von Willebrand factor binding protein on Staphylococcus aureus. Blood 96, 2149-2156PubMedGoogle Scholar
  38. Heden, L.O., Frithz, E. and Lindahl, G. (1991) Molecular characterization of an IgA receptor from group B streptococci: sequence of the gene, identification of a proline-rich region with unique structure and isolation of N-terminal fragments with IgA-binding capacity. Eur J Immunol 21, 1481-1490PubMedGoogle Scholar
  39. Herr, A.B., Ballister, E.R. and Bjorkman, P.J. (2003a) Insights into IgA-mediated immune responses from the crystal structures of human FcalphaRI and its complex with IgA1-Fc. Nature 423, 614-620Google Scholar
  40. Herr, A.B., White, C.L., Milburn, C., Wu, C. and Bjorkman, P.J. (2003b) Bivalent binding of IgA1 to FcalphaRI suggests a mechanism for cytokine activation of IgA phagocytosis. J Mol Biol 327, 645-657Google Scholar
  41. Higgs, R., Ni Gabhann, J., Ben Larbi, N., Breen, E.P., Fitzgerald, K.A. and Jefferies, C.A. (2008) The E3 ubiquitin ligase Ro52 negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. J Immunol 181, 1780-1786PubMedGoogle Scholar
  42. Ilowite, N.T., Wedgwood, J.F., Moore, T.L., Ramakrishnan, T. and Bonagura, V.R. (1991) Hidden rheumatoid factor and Wa idiotype expression in juvenile rheumatoid arthritis. Scand J Immunol 34, 453-460PubMedGoogle Scholar
  43. James, L.C., Keeble, A.H., Khan, Z., Rhodes, D.A. and Trowsdale, J. (2007) Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function. Proc Natl Acad Sci U S A 104, 6200-6205PubMedGoogle Scholar
  44. Jarvis, W.R., Schlosser, J., Chinn, R.Y., Tweeten, S. and Jackson, M. (2007) National prevalence of methicillin-resistant Staphylococcus aureus in inpatients at US health care facilities, 2006. Am J Infect Control 35, 631-637PubMedGoogle Scholar
  45. Johnson, D.C., Frame, M.C., Ligas, M.W., Cross, A.M. and Stow, N.D. (1988) Herpes simplex virus immunoglobulin G Fc receptor activity depends on a complex of two viral glycoproteins, gE and gI. J Virol 62, 1347-1354PubMedGoogle Scholar
  46. Keeble, A.H., Khan, Z., Forster, A. and James, L.C. (2008) TRIM21 is an IgG receptor that is structurally, thermodynamically, and kinetically conserved. Proc Natl Acad Sci U S A 105, 6045-6050PubMedGoogle Scholar
  47. Kikuno, K., Kang, D.W., Tahara, K., Torii, I., Kubagawa, H.M., Ho, K.J., Baudino, L., Nishizaki, N., Shibuya, A. and Kubagawa, H. (2007) Unusual biochemical features and follicular dendritic cell expression of human Fcalpha/mu receptor. Eur J Immunol 37, 3540-3550PubMedGoogle Scholar
  48. Kim, H.K., Cheng, A.G., Kim, H.Y., Missiakas, D.M. and Schneewind, O. (2010) Nontoxigenic protein A vaccine for methicillin-resistant Staphylococcus aureus infections in mice. J Exp Med 207, 1863-1870PubMedGoogle Scholar
  49. Kubagawa, H., Oka, S., Kubagawa, Y., Torii, I., Takayama, E., Kang, D.W., Gartland, G.L., Bertoli, L.F., Mori, H., Takatsu, H., Kitamura, T., Ohno, H. and Wang, J.Y. (2009) Identity of the elusive IgM Fc receptor (FcmuR) in humans. J Exp Med 206, 2779-2793PubMedGoogle Scholar
  50. Kuo, T.T., Baker, K., Yoshida, M., Qiao, S.W., Aveson, V.G., Lencer, W.I. and Blumberg, R.S. (2010) Neonatal Fc receptor: from immunity to therapeutics. J Clin Immunol 30, 777-789PubMedGoogle Scholar
  51. Lambris, J.D., Ricklin, D. and Geisbrecht, B.V. (2008) Complement evasion by human pathogens. Nat Rev Microbiol 6, 132-142PubMedGoogle Scholar
  52. Langley, R., Wines, B., Willoughby, N., Basu, I., Proft, T. and Fraser, J.D. (2005) The staphylococcal superantigen-like protein 7 binds IgA and complement C5 and inhibits IgA-Fc alpha RI binding and serum killing of bacteria. J Immunol 174, 2926-2933PubMedGoogle Scholar
  53. Laursen, N.S., Gordon, N., Hermans, S., Lorenz, N., Jackson, N., Wines, B., Spillner, E., Christensen, J.B., Jensen, M., Fredslund, F., Bjerre, M., Sottrup-Jensen, L., Fraser, J.D. and Andersen, G.R. (2010) Structural basis for inhibition of complement C5 by the SSL7 protein from Staphylococcus aureus. Proc Natl Acad Sci U S A 107, 3681-3686PubMedGoogle Scholar
  54. Leonetti, M., Galon, J., Thai, R., Sautes-Fridman, C., Moine, G. and Menez, A. (1999) Presentation of antigen in immune complexes is boosted by soluble bacterial immunoglobulin binding proteins. J Exp Med 189, 1217-1228PubMedGoogle Scholar
  55. Lindahl, G. and Akerstrom, B. (1989) Receptor for IgA in group A streptococci: cloning of the gene and characterization of the protein expressed in Escherichia coli. Mol Microbiol 3, 239-247PubMedGoogle Scholar
  56. Lindahl, G., Akerstrom, B., Vaerman, J.P. and Stenberg, L. (1990) Characterization of an IgA receptor from group B streptococci: specificity for serum IgA. Eur J Immunol 20, 2241-2247PubMedGoogle Scholar
  57. Lindsay, J.A. and Holden, M.T. (2006) Understanding the rise of the superbug: investigation of the evolution and genomic variation of Staphylococcus aureus. Funct Integr Genomics 6, 186-201PubMedGoogle Scholar
  58. Maliszewski, C.R., March, C.J., Schoenborn, M.A., Gimpel, S. and Shen, L. (1990) Expression cloning of a human Fc receptor for IgA. J Exp Med 172, 1665-1672PubMedGoogle Scholar
  59. Mallery, D.L., McEwan, W.A., Bidgood, S.R., Towers, G.J., Johnson, C.M. and James, L.C. (2010) Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21). Proc Natl Acad Sci U S A 107, 19985-19990PubMedGoogle Scholar
  60. Mannik, M., Nardella, F.A. and Sasso, E.H. (1988) Rheumatoid factors in immune complexes of patients with rheumatoid arthritis. Springer Semin Immunopathol 10, 215-230PubMedGoogle Scholar
  61. Martin, W.L., West, A.P., Jr., Gan, L. and Bjorkman, P.J. (2001) Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding. Mol Cell 7, 867-877PubMedGoogle Scholar
  62. Masuda, A., Yoshida, M., Shiomi, H., Morita, Y., Kutsumi, H., Inokuchi, H., Mizuno, S., Nakamura, A., Takai, T., Blumberg, R.S. and Azuma, T. (2009) Role of Fc Receptors as a therapeutic target. Inflamm Allergy Drug Targets 8, 80-86PubMedGoogle Scholar
  63. McNamara, C., Zinkernagel, A.S., Macheboeuf, P., Cunningham, M.W., Nizet, V. and Ghosh, P. (2008) Coiled-coil irregularities and instabilities in group A Streptococcus M1 are required for virulence. Science 319, 1405-1408PubMedGoogle Scholar
  64. Moiani, D., Salvalaglio, M., Cavallotti, C., Bujacz, A., Redzynia, I., Bujacz, G., Dinon, F., Pengo, P. and Fassina, G. (2009) Structural characterization of a Protein A mimetic peptide dendrimer bound to human IgG. J Phys Chem B 113, 16268-16275PubMedGoogle Scholar
  65. Monteiro, R.C. (2010) Role of IgA and IgA fc receptors in inflammation. J Clin Immunol 30, 1-9PubMedGoogle Scholar
  66. Monteiro, R.C. and Van De Winkel, J.G. (2003) IgA Fc receptors. Annu Rev Immunol 21, 177-204PubMedGoogle Scholar
  67. Morfeldt, E., Berggard, K., Persson, J., Drakenberg, T., Johnsson, E., Lindahl, E., Linse, S. and Lindahl, G. (2001) Isolated hypervariable regions derived from streptococcal M proteins specifically bind human C4b-binding protein: implications for antigenic variation. J Immunol 167, 3870-3877PubMedGoogle Scholar
  68. Nezlin, R. and Ghetie, V. (2004) Interactions of immunoglobulins outside the antigen-combining site. Adv Immunol 82, 155-215PubMedGoogle Scholar
  69. Niida, M., Tanaka, M. and Kamitani, T. (2010) Downregulation of active IKK beta by Ro52-mediated autophagy. Mol Immunol 47, 2378-2387PubMedGoogle Scholar
  70. Nitsche-Schmitz, D.P., Johansson, H.M., Sastalla, I., Reissmann, S., Frick, I.M. and Chhatwal, G.S. (2007) Group G streptococcal IgG binding molecules FOG and protein G have different impacts on opsonization by C1q. J Biol Chem 282, 17530-17536PubMedGoogle Scholar
  71. Nomura, Y., Sugiyama, S., Sakamoto, T., Miyakawa, S., Adachi, H., Takano, K., Murakami, S., Inoue, T., Mori, Y., Nakamura, Y. and Matsumura, H. (2010) Conformational plasticity of RNA for target recognition as revealed by the 2.15 A crystal structure of a human IgG-aptamer complex. Nucleic Acids Res 38, 7822-7829PubMedGoogle Scholar
  72. Ochsenbein, A.F. and Zinkernagel, R.M. (2000) Natural antibodies and complement link innate and acquired immunity. Immunol Today 21, 624-630PubMedGoogle Scholar
  73. Ozato, K., Yoshimi, R., Chang, T.H., Wang, H., Atsumi, T. and Morse, H.C., 3rd. (2009) Comment on “Gene disruption study reveals a nonredundant role for TRIM21/Ro52 in NF-kappa B-dependent cytokine expression in fibroblasts”. J Immunol 183, 7619; author reply 7720-7611Google Scholar
  74. Pasquier, B., Launay, P., Kanamaru, Y., Moura, I.C., Pfirsch, S., Ruffie, C., Henin, D., Benhamou, M., Pretolani, M., Blank, U. and Monteiro, R.C. (2005) Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM. Immunity 22, 31-42PubMedGoogle Scholar
  75. Persson, J., Beall, B., Linse, S. and Lindahl, G. (2006) Extreme sequence divergence but conserved ligand-binding specificity in Streptococcus pyogenes M protein. PLoS Pathog 2, e47PubMedGoogle Scholar
  76. Peterson, C., Malone, C.C. and Williams, R.C., Jr. (1995) Rheumatoid-factor-reactive sites on CH3 established by overlapping 7-mer peptide epitope analysis. Mol Immunol 32, 57-75PubMedGoogle Scholar
  77. Pfefferkorn, L.C. and Yeaman, G.R. (1994) Association of IgA-Fc receptors (Fc alpha R) with Fc epsilon RI gamma 2 subunits in U937 cells. Aggregation induces the tyrosine phosphorylation of gamma 2. J Immunol 153, 3228-3236PubMedGoogle Scholar
  78. Pleass, R.J., Areschoug, T., Lindahl, G. and Woof, J.M. (2001) Streptococcal IgA-binding proteins bind in the Calpha 2-Calpha 3 interdomain region and inhibit binding of IgA to human CD89. J Biol Chem 276, 8197-8204PubMedGoogle Scholar
  79. Ramsland, P.A. and Farrugia, W. (2002) Crystal structures of human antibodies: a detailed and unfinished tapestry of immunoglobulin gene products. J Mol Recognit 15, 248-259PubMedGoogle Scholar
  80. Ramsland, P.A., Farrugia, W., Bradford, T.M., Mark Hogarth, P. and Scott, A.M. (2004) Structural convergence of antibody binding of carbohydrate determinants in Lewis Y tumor antigens. J Mol Biol 340, 809-818PubMedGoogle Scholar
  81. Ramsland, P.A., Shan, L., Moomaw, C.R., Slaughter, C.A., Fan, Z., Guddat, L.W. and Edmundson, A.B. (2000) An unusual human IgM antibody with a protruding HCDR3 and high avidity for its peptide ligands. Mol Immunol 37, 295-310PubMedGoogle Scholar
  82. Ramsland, P.A., Terzyan, S.S., Cloud, G., Bourne, C.R., Farrugia, W., Tribbick, G., Geysen, H.M., Moomaw, C.R., Slaughter, C.A. and Edmundson, A.B. (2006) Crystal structure of a glycosylated Fab from an IgM cryoglobulin with properties of a natural proteolytic antibody. Biochem J 395, 473-481PubMedGoogle Scholar
  83. Ramsland, P.A., Willoughby, N., Trist, H.M., Farrugia, W., Hogarth, P.M., Fraser, J.D. and Wines, B.D. (2007) Structural basis for evasion of IgA immunity by Staphylococcus aureus revealed in the complex of SSL7 with Fc of human IgA1. Proc Natl Acad Sci U S A 104, 15051-15056PubMedGoogle Scholar
  84. Rhodes, D.A. and Trowsdale, J. (2007) TRIM21 is a trimeric protein that binds IgG Fc via the B30.2 domain. Mol Immunol 44, 2406-2414PubMedGoogle Scholar
  85. Rhodes, D.A., Ihrke, G., Reinicke, A.T., Malcherek, G., Towey, M., Isenberg, D.A. and Trowsdale, J. (2002) The 52 000 MW Ro/SS-A autoantigen in Sjogren’s syndrome/systemic lupus erythematosus (Ro52) is an interferon-gamma inducible tripartite motif protein associated with membrane proximal structures. Immunology 106, 246-256PubMedGoogle Scholar
  86. Roopenian, D.C. and Akilesh, S. (2007) FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 7, 715-725PubMedGoogle Scholar
  87. Roux, K.H., Strelets, L., Brekke, O.H., Sandlie, I. and Michaelsen, T.E. (1998) Comparisons of the ability of human IgG3 hinge mutants, IgM, IgE, and IgA2, to form small immune complexes: a role for flexibility and geometry. J Immunol 161, 4083-4090PubMedGoogle Scholar
  88. Roux, K.H., Strelets, L. and Michaelsen, T.E. (1997) Flexibility of human IgG subclasses. J Immunol 159, 3372-3382PubMedGoogle Scholar
  89. Rudolph, M.G., Stanfield, R.L. and Wilson, I.A. (2006) How TCRs bind MHCs, peptides, and coreceptors. Annu Rev Immunol 24, 419-466PubMedGoogle Scholar
  90. Sandin, C., Linse, S., Areschoug, T., Woof, J.M., Reinholdt, J. and Lindahl, G. (2002) Isolation and detection of human IgA using a streptococcal IgA-binding peptide. J Immunol 169, 1357-1364PubMedGoogle Scholar
  91. Sasso, E.H., Barber, C.V., Nardella, F.A., Yount, W.J. and Mannik, M. (1988) Antigenic specificities of human monoclonal and polyclonal IgM rheumatoid factors. The C gamma 2-C gamma 3 interface region contains the major determinants. J Immunol 140, 3098-3107PubMedGoogle Scholar
  92. Sauer-Eriksson, A.E., Kleywegt, G.J., Uhlen, M. and Jones, T.A. (1995) Crystal structure of the C2 fragment of streptococcal protein G in complex with the Fc domain of human IgG. Structure 3, 265-278PubMedGoogle Scholar
  93. Schmitt, R., Carlsson, F., Morgelin, M., Tati, R., Lindahl, G. and Karpman, D. (2010) Tissue deposits of IgA-binding streptococcal M proteins in IgA nephropathy and Henoch-Schonlein purpura. Am J Pathol 176, 608-618PubMedGoogle Scholar
  94. Shibuya, A., Sakamoto, N., Shimizu, Y., Shibuya, K., Osawa, M., Hiroyama, T., Eyre, H.J., Sutherland, G.R., Endo, Y., Fujita, T., Miyabayashi, T., Sakano, S., Tsuji, T., Nakayama, E., Phillips, J.H., Lanier, L.L. and Nakauchi, H. (2000) Fc alpha/mu receptor mediates endocytosis of IgM-coated microbes. Nat Immunol 1, 441-446PubMedGoogle Scholar
  95. Shima, H., Takatsu, H., Fukuda, S., Ohmae, M., Hase, K., Kubagawa, H., Wang, J.Y. and Ohno, H. (2010) Identification of TOSO/FAIM3 as an Fc receptor for IgM. Int Immunol 22, 149-156PubMedGoogle Scholar
  96. Simister, N.E. and Mostov, K.E. (1989) An Fc receptor structurally related to MHC class I antigens. Nature 337, 184-187PubMedGoogle Scholar
  97. Smeesters, P.R., McMillan, D.J. and Sriprakash, K.S. (2010) The streptococcal M protein: a highly versatile molecule. Trends Microbiol 18, 275-282PubMedGoogle Scholar
  98. Sprague, E.R., Wang, C., Baker, D. and Bjorkman, P.J. (2006) Crystal structure of the HSV-1 Fc receptor bound to Fc reveals a mechanism for antibody bipolar bridging. PLoS Biol 4, e148PubMedGoogle Scholar
  99. Takahata, M., Bohgaki, M., Tsukiyama, T., Kondo, T., Asaka, M. and Hatakeyama, S. (2008) Ro52 functionally interacts with IgG1 and regulates its quality control via the ERAD system. Mol Immunol 45, 2045-2054PubMedGoogle Scholar
  100. Tanaka, M. and Kamitani, T. (2010) Cytoplasmic relocation of Daxx induced by Ro52 and FLASH. Histochem Cell Biol 134, 297-306PubMedGoogle Scholar
  101. Tanaka, M., Tanji, K., Niida, M. and Kamitani, T. (2010) Dynamic movements of Ro52 cytoplasmic bodies along microtubules. Histochem Cell Biol 133, 273-284PubMedGoogle Scholar
  102. Thern, A., Stenberg, L., Dahlback, B. and Lindahl, G. (1995) Ig-binding surface proteins of Streptococcus pyogenes also bind human C4b-binding protein (C4BP), a regulatory component of the complement system. J Immunol 154, 375-386PubMedGoogle Scholar
  103. Van Der Steen, L., Tuk, C.W., Bakema, J.E., Kooij, G., Reijerkerk, A., Vidarsson, G., Bouma, G., Kraal, G., de Vries, H.E., Beelen, R.H. and van Egmond, M. (2009) Immunoglobulin A: Fc(alpha)RI interactions induce neutrophil migration through release of leukotriene B4. Gastroenterology 137, 2018-2029 e2011-2013PubMedGoogle Scholar
  104. West, A.P., Jr. and Bjorkman, P.J. (2000) Crystal structure and immunoglobulin G binding properties of the human major histocompatibility complex-related Fc receptor. Biochemistry 39, 9698-9708PubMedGoogle Scholar
  105. Williams, R.C., Jr. and Malone, C.C. (1994) Rheumatoid-factor-reactive sites on CH2 established by analysis of overlapping peptides of primary sequence. Scand J Immunol 40, 443-456PubMedGoogle Scholar
  106. Wines, B.D. and Hogarth, P.M. (2006) IgA receptors in health and disease. Tissue Antigens 68, 103-114PubMedGoogle Scholar
  107. Wines, B.D., Hulett, M.D., Jamieson, G.P., Trist, H.M., Spratt, J.M. and Hogarth, P.M. (1999) Identification of residues in the first domain of human Fc alpha receptor essential for interaction with IgA. J Immunol 162, 2146-2153PubMedGoogle Scholar
  108. Wines, B.D., Sardjono, C.T., Trist, H.H., Lay, C.S. and Hogarth, P.M. (2001) The interaction of Fc alpha RI with IgA and its implications for ligand binding by immunoreceptors of the leukocyte receptor cluster. J Immunol 166, 1781-1789PubMedGoogle Scholar
  109. Wines, B.D., Trist, H.M., Ramsland, P.A. and Hogarth, P.M. (2006a) A common site of the Fc receptor gamma subunit interacts with the unrelated immunoreceptors FcalphaRI and FcepsilonRI. J Biol Chem 281, 17108-17113Google Scholar
  110. Wines, B.D., Willoughby, N., Fraser, J.D. and Hogarth, P.M. (2006b) A competitive mechanism for staphylococcal toxin SSL7 inhibiting the leukocyte IgA receptor, Fc alphaRI, is revealed by SSL7 binding at the C alpha2/C alpha3 interface of IgA. J Biol Chem 281, 1389-1393Google Scholar
  111. Woof, J.M. and Kerr, M.A. (2006) The function of immunoglobulin A in immunity. J Pathol 208, 270-282PubMedGoogle Scholar
  112. Yang, K., Shi, H.X., Liu, X.Y., Shan, Y.F., Wei, B., Chen, S. and Wang, C. (2009) TRIM21 is essential to sustain IFN regulatory factor 3 activation during antiviral response. J Immunol 182, 3782-3792PubMedGoogle Scholar
  113. Yoshimi, R., Chang, T.H., Wang, H., Atsumi, T., Morse, H.C., 3rd and Ozato, K. (2009) Gene disruption study reveals a nonredundant role for TRIM21/Ro52 in NF-kappaB-dependent cytokine expression in fibroblasts. J Immunol 182, 7527-7538PubMedGoogle Scholar
  114. Yuriev, E., Ramsland, P.A. and Edmundson, A.B. (2001) Docking of combinatorial peptide libraries into a broadly cross-reactive human IgM. J Mol Recognit 14, 172-184PubMedGoogle Scholar
  115. Yuriev, E., Ramsland, P.A. and Edmundson, A.B. (2002) Recognition of IgG-derived peptides by a human IgM with an unusual combining site. Scand J Immunol 55, 242-255PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Bruce D. Wines
    • 1
    • 2
    • 3
  • Halina M. Trist
    • 1
  • William Farrugia
    • 1
  • Chloe Ngo
    • 1
    • 2
  • John Trowsdale
    • 4
  • Thomas Areschoug
    • 5
  • Gunnar Lindahl
    • 5
  • John D. Fraser
    • 6
  • Paul A. Ramsland
    • 1
    • 3
    • 7
    Email author
  1. 1.Centre for ImmunologyBurnet InstituteMelbourneAustralia
  2. 2.Department of PathologyUniversity of MelbourneMelbourneAustralia
  3. 3.Department of ImmunologyMonash UniversityMelbourneAustralia
  4. 4.Department of Pathology, Immunology Division, Cambridge Institute for Medical ResearchUniversity of CambridgeCambridgeUK
  5. 5.Department of Laboratory Medicine, Division of Medical MicrobiologyLund UniversityLundSweden
  6. 6.School of Medical Sciences and Maurice Wilkins Centre of ExcellenceUniversity of AucklandAucklandNew Zealand
  7. 7.Centre for ImmunologyBurnet InstituteMelbourneAustralia

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