Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Insights into IgA-mediated immune responses from the crystal structures of human FcαRI and its complex with IgA1-Fc

Nature volume 423, pages 614–620 (2003)Cite this article

Abstract

Immunoglobulin-α (IgA)-bound antigens induce immune effector responses by activating the IgA-specific receptor FcαRI (CD89) on immune cells. Here we present crystal structures of human FcαRI alone and in a complex with the Fc region of IgA1 (Fcα). FcαRI has two immunoglobulin-like domains that are oriented at approximately right angles to each other. Fcα resembles the Fcs of immunoglobulins IgG and IgE, but has differently located interchain disulphide bonds and external rather than interdomain N-linked carbohydrates. Unlike 1:1 FcγRIII:IgG and FcɛRI:IgE complexes, two FcαRI molecules bind each Fcα dimer, one at each Cα2–Cα3 junction. The FcαRI-binding site on IgA1 overlaps the reported polymeric immunoglobulin receptor (pIgR)-binding site, which might explain why secretory IgA cannot initiate phagocytosis or bind to FcαRI-expressing cells in the absence of an integrin co-receptor.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: FcαRI structure.
Figure 2: Fcα structure.
Figure 3: FcαRI:Fcα structure.
Figure 4: FcαRI:Fcα interface.
Figure 5: Alignment of antibody Fc sequences.

Similar content being viewed by others

References

  1. Monteiro, R. C. & Van De Winkel, J. G. IgA Fc receptors. Annu. Rev. Immunol. 21, 177–204 (2003)

    Article  CAS  Google Scholar 

  2. Brandtzaeg, P. et al. Regional specialization in the mucosal immune system: what happens in the microcompartments? Immunol. Today 20, 141–151 (1999)

    Article  CAS  Google Scholar 

  3. Norderhaug, I. N., Johansen, F. E., Schjerven, H. & Brandtzaeg, P. Regulation of the formation and external transport of secretory immunoglobulins. Crit. Rev. Immunol. 19, 481–508 (1999)

    CAS  PubMed  Google Scholar 

  4. Monteiro, R. C., Kubagawa, H. & Cooper, M. D. Cellular distribution, regulation, and biochemical nature of an Fcα receptor in humans. J. Exp. Med. 171, 597–613 (1990)

    Article  CAS  Google Scholar 

  5. Vidarsson, G. et al. Activity of human IgG and IgA subclasses in immune defense against Neisseria meningitidis serogroup B. J. Immunol. 166, 6250–6256 (2001)

    Article  CAS  Google Scholar 

  6. van Egmond, M. et al. FcαRI-positive liver Kupffer cells: reappraisal of the function of immunoglobulin A in immunity. Nature Med. 6, 680–685 (2000)

    Article  CAS  Google Scholar 

  7. van Spriel, A. B. et al. Mac-1 (CD11b/CD18) is essential for Fc receptor-mediated neutrophil cytotoxicity and immunologic synapse formation. Blood 97, 2478–2486 (2001)

    Article  CAS  Google Scholar 

  8. Motegi, Y. & Kita, H. Interaction with secretory component stimulates effector functions of human eosinophils but not of neutrophils. J. Immunol. 161, 4340–4346 (1998)

    CAS  PubMed  Google Scholar 

  9. Wende, H., Colonna, M., Ziegler, A. & Volz, A. Organization of the leukocyte receptor cluster (LRC) on human chromosome 19q13.4. Mamm. Genome 10, 154–160 (1999)

    Article  CAS  Google Scholar 

  10. Garman, S. C., Wurzburg, B. A., Tarchevskaya, S. S., Kinet, J. P. & Jardetzky, T. S. Structure of the Fc fragment of human IgE bound to its high-affinity receptor FcɛRIα. Nature 406, 259–266 (2000)

    Article  ADS  CAS  Google Scholar 

  11. Sondermann, P., Huber, R., Oosthuizen, V. & Jacob, U. The 3.2-Å crystal structure of the human IgG1 Fc fragment-FcγRIII complex. Nature 406, 267–273 (2000)

    Article  ADS  CAS  Google Scholar 

  12. Herr, A. B., White, C. L., Milburn, C., Wu, C. & Bjorkman, P. J. Bivalent binding of IgA1 to FcαRI suggests a mechanism for cytokine activation of IgA phagocytosis. J. Mol. Biol. 327, 645–657 (2003)

    Article  CAS  Google Scholar 

  13. Pleass, R. J., Dunlop, J. I., Anderson, C. M. & Woof, J. M. Identification of residues in the CH2/CH3 domain interface of IgA essential for interaction with the human Fcα receptor (FcαR) CD89. J. Biol. Chem. 274, 23508–23514 (1999)

    Article  CAS  Google Scholar 

  14. Carayannopoulos, L., Hexham, J. M. & Capra, J. D. Localization of the binding site for the monocyte immunoglobulin (Ig) A-Fc receptor (CD89) to the domain boundary between Cα2 and Cα3 in human IgA1. J. Exp. Med. 183, 1579–1586 (1996)

    Article  CAS  Google Scholar 

  15. Martin, W. L., West, A. P. Jr, Gan, L. & Bjorkman, P. J. Crystal structure at 2.8 Å of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding. Mol. Cell 7, 867–877 (2001)

    Article  CAS  Google Scholar 

  16. Chapman, T. L., Heikema, A. P., West, A. P. & Bjorkman, P. J. Crystal structure and ligand binding properties of the D1D2 region of the inhibitory receptor LIR-1 (ILT2). Immunity 13, 727–736 (2000)

    Article  CAS  Google Scholar 

  17. Garman, S. C., Kinet, J. P. & Jardetzky, T. S. Crystal structure of the human high-affinity IgE receptor. Cell 95, 951–961 (1998)

    Article  CAS  Google Scholar 

  18. Maxwell, K. F. et al. Crystal structure of the human leukocyte Fc receptor, FcγRIIa. Nature Struct. Biol. 6, 437–442 (1999)

    Article  CAS  Google Scholar 

  19. Sondermann, P., Huber, R. & Jacob, U. Crystal structure of the soluble form of the human Fcγ-receptor IIb: a new member of the immunoglobulin superfamily at 1.7 Å resolution. EMBO J. 18, 1095–1103 (1999)

    Article  CAS  Google Scholar 

  20. Fan, Q. R. et al. Structure of the inhibitory receptor for human natural killer cells resembles haematopoietic receptors. Nature 389, 96–100 (1997)

    Article  ADS  CAS  Google Scholar 

  21. Huber, R., Deisenhofer, J., Colman, P. M., Matsushima, M. & Palm, W. Crystallographic structure studies of an IgG molecule and an Fc fragment. Nature 264, 415–420 (1976)

    Article  ADS  CAS  Google Scholar 

  22. Wan, T. et al. The crystal structure of IgE Fc reveals an asymmetrically bent conformation. Nature Immunol. 3, 681–686 (2002)

    Article  CAS  Google Scholar 

  23. Wurzburg, B. A., Garman, S. C. & Jardetzky, T. S. Structure of the human IgE-Fc Cɛ3-Cɛ4 reveals conformational flexibility in the antibody effector domains. Immunity 13, 375–385 (2000)

    Article  CAS  Google Scholar 

  24. Putnam, F. W., Liu, Y. S. & Low, T. L. Primary structure of a human IgA1 immunoglobulin. IV. Streptococcal IgA1 protease, digestion, Fab and Fc fragments, and the complete amino acid sequence of the α1 heavy chain. J. Biol. Chem. 254, 2865–2874 (1979)

    CAS  PubMed  Google Scholar 

  25. Yang, C., Kratzin, H., Gotz, H. & Hilschmann, N. Rule of antibody structure. Primary structure of a human monoclonal IgA-immunoglobulin (myeloma protein Tro). VII. Purification and characterization of the disulfide bridges. Hoppe-Seyler's Z. Physiol. Chem. 360, 1919–1940 (1979)

    CAS  PubMed  Google Scholar 

  26. Morton, H. C. et al. Immunoglobulin-binding sites of human FcαRI (CD89) and bovine Fcγ2R are located in their membrane-distal extracellular domains. J. Exp. Med. 189, 1715–1722 (1999)

    Article  CAS  Google Scholar 

  27. Wines, B. D. et al. Identification of residues in the first domain of human Fcα receptor essential for interaction with IgA. J. Immunol. 162, 2146–2153 (1999)

    CAS  PubMed  Google Scholar 

  28. Wines, B. D., Sardjono, C. T., Trist, H. M., Lay, C. S. & Hogarth, P. M. The interaction of FcαRI with IgA and its implications for ligand binding by immunoreceptors of the leukocyte receptor cluster. J. Immunol. 166, 1781–1789 (2001)

    Article  CAS  Google Scholar 

  29. Garman, S. C., Sechi, S., Kinet, J. P. & Jardetzky, T. S. The analysis of the human high affinity IgE receptor FcɛRIα from multiple crystal forms. J. Mol. Biol. 311, 1049–1062 (2001)

    Article  CAS  Google Scholar 

  30. Deisenhofer, J. 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-Å resolution. Biochemistry 20, 2361–2370 (1981)

    Article  CAS  Google Scholar 

  31. Sauer-Eriksson, A. E., Kleywegt, G. J., Uhlen, M. & Jones, T. A. Crystal structure of the C2 fragment of streptococcal protein G in complex with the Fc domain of human IgG. Structure 3, 265–278 (1995)

    Article  CAS  Google Scholar 

  32. Corper, A. L. et al. Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a novel topology of antibody–antigen interaction. Nature Struct. Biol. 4, 374–381 (1997)

    Article  CAS  Google Scholar 

  33. DeLano, W. L., Ultsch, M. H., de Vos, A. M. & Wells, J. A. Convergent solutions to binding at a protein–protein interface. Science 287, 1279–1283 (2000)

    Article  ADS  CAS  Google Scholar 

  34. Saphire, E. O. et al. Contrasting IgG structures reveal extreme asymmetry and flexibility. J. Mol. Biol. 319, 9–18 (2002)

    Article  CAS  Google Scholar 

  35. Shogren, R., Gerken, T. A. & Jentoft, N. Role of glycosylation on the conformation and chain dimensions of O-linked glycoproteins: light-scattering studies of ovine submaxillary mucin. Biochemistry 28, 5525–5536 (1989)

    Article  CAS  Google Scholar 

  36. Iikura, M. et al. Secretory IgA induces degranulation of IL-3-primed basophils. J. Immunol. 161, 1510–1515 (1998)

    CAS  PubMed  Google Scholar 

  37. Hexham, J. M. et al. A human immunoglobulin (Ig)A Cα3 domain motif directs polymeric Ig receptor-mediated secretion. J. Exp. Med. 189, 747–752 (1999)

    Article  CAS  Google Scholar 

  38. White, K. D. & Capra, J. D. Targeting mucosal sites by polymeric immunoglobulin receptor-directed peptides. J. Exp. Med. 196, 551–555 (2002)

    Article  CAS  Google Scholar 

  39. Bracke, M., Lammers, J. W., Coffer, P. J. & Koenderman, L. Cytokine-induced inside-out activation of FcαR (CD89) is mediated by a single serine residue (S263) in the intracellular domain of the receptor. Blood 97, 3478–3483 (2001)

    Article  CAS  Google Scholar 

  40. Weisbart, R. H., Kacena, A., Schuh, A. & Golde, D. W. GM-CSF induces human neutrophil IgA-mediated phagocytosis by an IgA Fc receptor activation mechanism. Nature 332, 647–648 (1988)

    Article  ADS  CAS  Google Scholar 

  41. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997)

    Article  CAS  Google Scholar 

  42. Terwilliger, T. C. & Berendzen, J. Automated MAD and MIR structure solution. Acta Crystallogr. D 55, 849–861 (1999)

    Article  CAS  Google Scholar 

  43. De La Fortelle, E. & Bricogne, G. Maximum-likelihood heavy-atom parameter refinement for multiple isomorphous replacement and multiwavelength anomalous diffraction methods. Methods Enzymol. 276, 472–494 (1997)

    Article  CAS  Google Scholar 

  44. Collaborative Computational Project No. 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994)

    Article  Google Scholar 

  45. Brunger, A. T. et al. Crystallography & NMR system: a new software suite for macromolecular structure determination. Acta Crystallogr. D 54, 905–921 (1998)

    Article  CAS  Google Scholar 

  46. Navaza, J. AMoRe: an automated package for molecular replacement. Acta Crystallogr. A 50, 157–163 (1994)

    Article  Google Scholar 

  47. McDonald, I. K. & Thornton, J. M. Satisfying hydrogen bonding potential in proteins. J. Mol. Biol. 238, 777–793 (1994)

    Article  CAS  Google Scholar 

  48. Su, X. D. et al. Crystal structure of hemolin: a horseshoe shape with implications for homophilic adhesion. Science 281, 991–995 (1998)

    Article  ADS  CAS  Google Scholar 

  49. Kraulis, P. J. MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures. J. Appl. Crystallogr. 24, 946–950 (1991)

    Article  Google Scholar 

  50. Merritt, E. A. & Murphy, M. E. P. Raster3D Version 2.0, a program for photorealistic molecular graphics. Acta Crystallogr. D 50, 869–873 (1994)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank E. R. Sprague for help with data collection; E. R. Sprague, L. M. Thomas, A. P. West and K. Locher for discussions; P. M. Snow and the Caltech Protein Expression Facility for FcαRI expression; C. L. White for initial FcαRI crystallization trials; staff of the Stanford Synchrotron Radiation Laboratory for technical support; and G. Waksman, M. J. Bennett, W. L. Martin and members of the Bjorkman laboratory for comments on the manuscript. This work was supported by funds from the Damon Runyon Cancer Research Foundation (to A.B.H.), the Howard Hughes Medical Institute (to P.J.B.) and the Ralph M. Parsons Foundation for computational support.

Author information

Author notes

  1. Pamela J. Bjorkman

    Present address: University of California at Berkeley, Berkeley, California, 94720, USA

Authors and Affiliations

  1. Division of Biology 114-96, California Institute of Technology, Pasadena, California, 91125, USA

    Andrew B. Herr, Edward R. Ballister & Pamela J. Bjorkman

  2. Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, 91125, USA

    Edward R. Ballister

  3. La Salle High School, Pasadena, California, 91107, USA

    Edward R. Ballister

Authors
  1. Andrew B. Herr
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edward R. Ballister
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pamela J. Bjorkman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pamela J. Bjorkman.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

41586_2003_BFnature01685_MOESM1_ESM.doc

Supplementary Tables: Table 1: Crystallographic statistics Table 2: RMS deviations between FcαRI or Fcα and related proteinsTable 3: Pairwise interactions in the FcαRI:Fcα interface (DOC 131 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Herr, A., Ballister, E. & Bjorkman, P. Insights into IgA-mediated immune responses from the crystal structures of human FcαRI and its complex with IgA1-Fc. Nature 423, 614–620 (2003). https://doi.org/10.1038/nature01685

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01685

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing