Skip to main content

Thank you for visiting 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.

  • Letter
  • Published:

Three-finger toxin fold for the extracellular ligand-binding domain of the type II activin receptor serine kinase.


The transforming growth factor β (TGFβ) superfamily of cytokines elicit diverse biological responses by interacting with two distinct, but structurally related transmembrane receptor serine kinases (type I and type II). The binding of these dimeric ligands to the type II receptor is the first event in transmembrane signaling for this family. Here we report the 1.5 Å resolution crystal structure of the extracellular ligand-binding domain of the type II activin receptor (ActRII-ECD), which reveals a fold similar to that of a class of toxins known as three-finger toxins. This fold is primarily dictated by disulfide bonds formed by eight conserved cysteines, with a characteristic spacing, and thus is likely to be shared by most of the type I and II receptors for the TGFβ family. Sequence comparison with an evolutionarily distant activin binding-protein identifies several conserved residues, including two hydrophobic clusters that may form binding surfaces for activin and the type I receptor.

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

Access options

Buy this article

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

Figure 1: a, Stereo ribbon diagram of ActRII-ECD. The strands are numbered in the order that they occur in the sequence.
Figure 2: Alignment between six receptor ECD sequences and cardiotoxin.
Figure 3: Molecular surface representations of ActRII-ECD by GRASP29 showing the conserved features.
Figure 4: Stereo diagram of the experimental electron density maps in the region of the five disulfide bonds in molecule B.

Similar content being viewed by others

Accession codes


Protein Data Bank


  1. Kessler, D.S. & Melton, D.A. Science 266, 596–604 (1994).

    Article  CAS  Google Scholar 

  2. Vale, W., Hseuh, A., Rivier, C. & Yu, J. In Peptide growth factors and their receptors (eds Sporn, M. & Roberts, A.) 211– 248 (Springer-Verlag, Berlin; 1990).

    Book  Google Scholar 

  3. Vale, W. et al. Nature 321, 776–779 (1986).

    Article  CAS  Google Scholar 

  4. Mathews, L.S. & Vale, W.W. Cell 65, 973 –982 (1991).

    Article  CAS  Google Scholar 

  5. Mathews, L.S. & Vale, W.W. Receptor 3, 173–181 (1993).

    CAS  PubMed  Google Scholar 

  6. Wrana, J.L., Attisano, L., Wieser, R., Ventura, F. & Massague, J. Nature 370, 341– 347 (1994).

    Article  CAS  Google Scholar 

  7. Attisano, L., Wrana, J.L., Montalvo, E. & Massague, J. Mol. Cell. Biol. 16, 1066–1073 (1996).

    Article  CAS  Google Scholar 

  8. Lebrun, J.J. & Vale, W.W. Mol. Cell. Biol. 17, 1682–1691 (1997).

    Article  CAS  Google Scholar 

  9. Donaldson, C.J., Vaughan, J.M., Corrigan, A.C., Fischer, W.H. & Vale, W.W. Endocrinology in the press.

  10. Greenwald, J. et al. Biochemistry, 37, 16711– 16718 (1998).

    Article  CAS  Google Scholar 

  11. Ruberte, E., Marty, T., Nellen, D., Affolter, M. & Basler, K. Cell 80, 889– 897 (1995).

    Article  CAS  Google Scholar 

  12. Childs, S.R., Wrana, J.L., Arora, K., Attisano, L., O'Connor, M.B. & Massague, J. Proc. Natl. Acad. Sci. USA 90, 9475– 9479 (1993).

    Article  CAS  Google Scholar 

  13. Rees, B. & Bilwes, A. Chem. Res. Toxicol. 6, 385–406 (1993).

    Article  CAS  Google Scholar 

  14. McDonald, N.Q. & Hendrickson, W.A. Cell 73, 421–424 (1993).

    Article  CAS  Google Scholar 

  15. Schlunegger, M.P. & Grütter, M.G. Nature 358, 430–434 (1992).

    Article  CAS  Google Scholar 

  16. Daopin, S., Piez, K.A., Ogawa, Y. & Davies, D.R. Science 257, 369–373 (1992).

    Article  CAS  Google Scholar 

  17. Young, L., Jernigan, R.L. & Covell, D.G. Prot. Sci. 3, 717– 729 (1994).

    Article  CAS  Google Scholar 

  18. Clackson, T. & Wells, J.A. Science 267, 383–386 (1995).

    Article  CAS  Google Scholar 

  19. Janin, J. & Chothia, C. J. Biol. Chem. 265, 16027–16030 (1990).

    CAS  PubMed  Google Scholar 

  20. Yeates, T.O. Meth. Enz. 276, 344–358 (1997).

    Article  CAS  Google Scholar 

  21. Otwinowski, Z. in Proceedings of the CCP4 study weekend (eds Sawyer, L., Isaacs, N. & Burley, S.) 56–62 (Daresbury Laboratory, Warrington, UK; 1993).

    Google Scholar 

  22. Collaborative Computational Project No. 4. Acta Crystallogr. D 50, 760–776 (1994).

  23. Kleywegt, G. & Jones, T.A. In From first map to final model (eds Bailey, S., Hubbard, R. & Waller, D.) 59– 66 (Daresbury Laboratory, Warrington, UK; 1994).

    Google Scholar 

  24. Perrakis, A., Sixma, T.K., Wilson, K. & Lamzin, V.S. Acta Crystallogr. D 53, 448–455 (1997).

    Article  CAS  Google Scholar 

  25. Jones, T.A., Zou, J.Y., Cowan, S.W. & Kjeldgaard, M. Acta Crystallogr. A 47, 100–119 (1991).

    Google Scholar 

  26. Bilwes, A., Rees, B., Moras, D., Menez, R. & Menez, A. J. Mol. Biol. 239, 122– 136 (1994).

    Article  CAS  Google Scholar 

  27. Evans, S.V. J. Mol. Graphics 11, 134–138 (1993).

    Article  CAS  Google Scholar 

  28. Barton, G.J. Prot. Engng. 6, 37–40 (1993).

    Article  CAS  Google Scholar 

  29. Nicholls, A., Sharp, K.A. & Honig, B. Proteins Struct. Funct. Genet. 11, 281–296 (1991).

    Article  CAS  Google Scholar 

Download references


We thank G. Louie, R. Robinson and T. Hunter for helpful discussions and comments on the manuscript; H. Bellamy at SSRL and T. Earnest at ALS for help with data collection. SSRL and ALS are operated by the Department of Energy, Office of Basic Energy Sciences. The SSRL Biotechnology Program is supported by the National Institutes of Health, National Center for Research Resources, Biomedical Technology Program, and by the Department of Energy, Office of Biological and Environmental Research. J.G. is a Howard Hughes Medical Institute Predoctoral Fellow and Markey Fellow. S.C. is a recipient of a Klingenstein Fellowship Award in Neuroscience. This work was supported by a grant from the NIH.Correspondence should be addressed to S.C.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Senyon Choe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Greenwald, J., Fischer, W., Vale, W. et al. Three-finger toxin fold for the extracellular ligand-binding domain of the type II activin receptor serine kinase.. Nat Struct Mol Biol 6, 18–22 (1999).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


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