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Ligand–receptor binding revealed by the TNF family member TALL-1

Abstract

The tumour necrosis factor (TNF) ligand TALL-1 and its cognate receptors, BCMA, TACI and BAFF-R, were recently identified as members of the TNF superfamily, which are essential factors contributing to B-cell maturation. The functional, soluble fragment of TALL-1 (sTALL-1) forms a virus-like assembly for its proper function. Here we determine the crystal structures of sTALL-1 complexed with the extracellular domains of BCMA and BAFF-R at 2.6 and 2.5 Å, respectively. The single cysteine-rich domain of BCMA and BAFF-R both have saddle-like architectures, which sit on the horseback-like surface formed by four coil regions on each individual sTALL-1 monomer. Three novel structural modules, D2, X2 and N, were revealed from the current structures. Sequence alignments, structural modelling and mutagenesis revealed that one disulphide bridge in BAFF-R is critical for determining the binding specificity of the extracellular domain eBAFF-R to TALL-1 instead of APRIL, a closely related ligand of TALL-1, which was confirmed by binding experiments in vitro.

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Figure 1: Structures of eBCMA and eBAFF-R.
Figure 2: Overall structure of cBCMA with or without sTALL-1.
Figure 3: Comparison of different CRDs.
Figure 4: Detailed interactions of the two complexes.
Figure 5: Characterization of ligand specificity of BAFF-R.

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References

  1. Locksley, R. M., Killeen, N. & Lenardo, M. J. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104, 487–501 (2001)

    Article  CAS  Google Scholar 

  2. Shu, H. B., Hu, W. H. & Johnson, H. TALL-1 is a novel member of the TNF family that is downregulated by mitogens. J. Leukocyte Biol. 65, 680–683 (1999)

    Article  CAS  Google Scholar 

  3. Schneider, P. et al. BAFF, a novel ligand of the tumour necrosis factor family, stimulates B cell growth. J. Exp. Med. 189, 1747–1756 (1999)

    Article  CAS  Google Scholar 

  4. Moore, P. A. et al. BlyS: member of the tumour necrosis factor family and B lymphocyte stimulator. Science 285, 260–263 (1999)

    Article  CAS  Google Scholar 

  5. Mukhopadhyay, A., Ni, J., Zhai, Y., Yu, G. L. & Aggarwal, B. B. Identification and characterization of a novel cytokine, THANK, a TNF homologue that activates apoptosis, nuclear factor-κB, and c-Jun NH2-terminal kinase. J. Biol. Chem. 274, 15978–15981 (1999)

    Article  CAS  Google Scholar 

  6. Shu, H. B. & Johnson, H. B cell maturation protein is a receptor for the TNF family member TALL-1. Proc. Natl Acad. Sci. USA 97, 9156–9161 (2000)

    Article  ADS  CAS  Google Scholar 

  7. Gross, J. A. et al. TACI and BCMA are receptors for a TNF homologue implicated in B cell autoimmune disease. Nature 404, 995–999 (2000)

    Article  ADS  CAS  Google Scholar 

  8. Thompson, J. S. et al. BAFF binds to the tumour necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population. J. Exp Med. 192, 129–135 (2000)

    Article  CAS  Google Scholar 

  9. Marsters, S. A. et al. Interaction of the TNF homologues BLyS and APRIL with the TNF receptor homologues BCMA and TACI. Curr. Biol. 10, 785–788 (2000)

    Article  CAS  Google Scholar 

  10. Xia, X. Z. et al. TACI is a TRAF-interacting receptor for TALL-1, a tumour necrosis factor family member involved in B cell regulation. J. Exp. Med. 192, 137–143 (2000)

    Article  CAS  Google Scholar 

  11. Yan, M. et al. Identification of a receptor for BLyS demonstrates a crucial role in humoral immunity. Nature Immunol. 1, 37–41 (2000)

    Article  CAS  Google Scholar 

  12. Mackay, F. et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J. Exp. Med. 190, 1697–1710 (1999)

    Article  CAS  Google Scholar 

  13. Khare, S. D. et al. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc. Natl Acad. Sci. USA 97, 3370–3375 (2000)

    Article  ADS  CAS  Google Scholar 

  14. Thompson, J. S. et al. BAFF-R, a novel TNF receptor that specifically interacts with BAFF. Science 293, 2108–2111 (2001)

    Article  ADS  CAS  Google Scholar 

  15. Yan, M. et al. Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B cell deficiency. Curr. Biol. 11, 1547–1552 (2001)

    Article  CAS  Google Scholar 

  16. Schiemann, B. et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293, 2111–2114 (2001)

    Article  ADS  CAS  Google Scholar 

  17. Gross, J. A. et al. TACI-Ig neutralizes molecules critical for B-cell development and autoimmune disease. Impaired B-cell maturation in mice lacking BlyS. Immunity 15, 289–302 (2001)

    Article  CAS  Google Scholar 

  18. Xu, S. & Lam, K.-P. B-cell maturation protein, which binds the tumour necrosis factor family members BAFF and APRIL, is dispensable for humoral immune response. Mol. Cell. Biol. 21, 4067–4074 (2001)

    Article  CAS  Google Scholar 

  19. Von Bulow, G. U., van Deursen, J. M. & Bram, R. J. Regulation of the T-independent humoral response by TACI. Immunity 14, 573–582 (2001)

    Article  CAS  Google Scholar 

  20. Hahne, M. et al. APRIL, a new ligand of the tumour necrosis factor family, stimulates tumour cell growth. J. Exp. Med. 188, 1185–1190 (1998)

    Article  CAS  Google Scholar 

  21. Schneider, P. et al. Maturation of marginal zone and follicular B cells requires B cell activation factor of the tumour necrosis factor family and is independent of B cell maturation antigen. J. Exp. Med. 194, 1691–1697 (2001)

    Article  CAS  Google Scholar 

  22. Mackay, F. & Mackay, C. R. The role of BAFF in B-cell maturation, T-cell activation and autoimmunity. Trends Immunol. 23, 113–115 (2002)

    Article  CAS  Google Scholar 

  23. Jones, E. Y., Stuart, D. I. & Walker, N. P. Structure of tumour necrosis factor. Nature 338, 225–228 (1989)

    Article  ADS  CAS  Google Scholar 

  24. Eck, M. J. & Sprang, S. R. The structure of tumour necrosis factor-α at 2.6 Å resolution: implications for receptor binding. J. Biol. Chem. 264, 17595–17605 (1989)

    CAS  PubMed  Google Scholar 

  25. Eck, M. J., Ultsch, M., Rinderknecht, E., de Vos, A. M. & Sprang, S. R. The structure of human lymphotoxin (tumour necrosis factor β) at 1.9 Å resolution. J. Biol. Chem. 267, 2119–2122 (1992)

    CAS  PubMed  Google Scholar 

  26. Karpusas, M. et al. 2 Å crystal structure of an extracellular fragment of human CD40 ligand. Structure 3, 1031–1039 (1995)

    Article  CAS  Google Scholar 

  27. Cha, S. S. et al. 2.8 Å resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity. Immunity 11, 253–261 (1999)

    Article  CAS  Google Scholar 

  28. Lam, J., Nelson, C. A., Ross, F. P., Teitelbaum, S. L. & Fremont, D. H. Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor–ligand specificity. J. Clin. Invest. 108, 971–979 (2001)

    Article  CAS  Google Scholar 

  29. Karpusas, M. et al. Crystal structure of extracellular human BAFF, a TNF family member that stimulates B lymphocytes. J. Mol. Biol. 315, 1145–1154 (2002)

    Article  CAS  Google Scholar 

  30. Oren, D. A. et al. Structural basis of BlyS receptor recognition. Nature Struct. Biol. 9, 288–292 (2002)

    Article  CAS  Google Scholar 

  31. Liu, Y. et al. Crystal structure of sTALL-1 reveals a virus-like assembly of TNF family ligands. Cell 108, 383–394 (2002)

    Article  CAS  Google Scholar 

  32. Banner, D. W. et al. Crystal structure of the soluble human 55 kd TNF receptor–human TNF complex: implications for TNF receptor activation. Cell 73, 431–445 (1993)

    Article  CAS  Google Scholar 

  33. Mongkolsapaya, J. et al. Structure of the TRAIL–DR5 complex reveals mechanisms conferring specificity in apoptotic initiation. Nature Struct. Biol. 6, 1048–1053 (1999)

    Article  CAS  Google Scholar 

  34. Hymowitz, S. G. et al. Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Mol. Cell 4, 563–571 (1999)

    Article  CAS  Google Scholar 

  35. Yu, G. et al. APRIL and TALL-1 and receptors BCMA and TACI: system for regulating humoral immunity. Nature Immunol. 1, 252–256 (2000)

    Article  CAS  Google Scholar 

  36. Naismith, J. H. & Sprang, S. R. Modularity in the TNF-receptor family. Trends Biochem. Sci. 23, 74–79 (1998)

    Article  CAS  Google Scholar 

  37. Bodmer, J. L., Schneider, P. & Tschopp, J. The molecular architecture of the TNF superfamily. Trends Biochem. Sci. 27, 19–26 (2002)

    Article  CAS  Google Scholar 

  38. Kayagaki, N. et al. BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-κB2. Immunity 17, 515–524 (2002)

    Article  CAS  Google Scholar 

  39. Ware, C. F. APRIL and BAFF connect autoimmunity and cancer. J. Exp. Med. 192, F35–F37 (2000)

    Article  CAS  Google Scholar 

  40. Brunger, A. T. et al. Crystallography and NMR System (CNS): A new software system for macromolecular structure determination. Acta Crystallogr. D 54, 905–921 (1998)

    Article  CAS  Google Scholar 

  41. Roschke, V. et al. BlyS and APRIL form biologically active heterotrimers that are expressed in patients with systemic immune-based rheumatic diseases. J. Immunol. 169, 4314–4321 (2002)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  43. Jones, T. A., Zou, J.-Y., Cowan, S. & Kjeldgaard, A. L. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991)

    Article  Google Scholar 

  44. Carson, M. Ribbon models of macromolecules. Methods Enzymol. 277, 493–505 (1997)

    Article  CAS  Google Scholar 

  45. Esnouf, R. M. BobScript v2.4 changes (C). J. Mol. Graphics 15, 132–134 (1997)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Zhao, O. Swartz and L. Halton for reading our manuscript; Z. Chen for Fig. 5f; M. Carson, S. R. Sprang, C. R. Mackay and J. Tschopp for their suggestions; the Howard Hughes Medical Institute, Zuckerman/Canyon Ranch and A. Lapporte for the support of our X-ray and computing facility; A. Joachimiak and SBC (ID-19) at APS for high-resolution data; and P. C. Marrack, J. D. Crapo, J. Cambier, X. Liu and other members at the National Jewish Medical and Research Center for support. S.H.B. is supported by an NIH grant and the Arthritis Foundation; Y.L. is supported partly by a Priscilla Campbell Memorial Fellowship; X.H. is supported partly by a Janet S. Lewald fellowship; G.Z. is supported by a PEW Scholar Award, a start-up fund from National Jewish Medical and Research Center and the Cancer League of Colorado, Inc.; P.M. and G.Z. are supported by NIH grants.

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Correspondence to Gongyi Zhang.

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Liu, Y., Hong, X., Kappler, J. et al. Ligand–receptor binding revealed by the TNF family member TALL-1. Nature 423, 49–56 (2003). https://doi.org/10.1038/nature01543

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