Abstract
Bone morphogenetic proteins (BMPs) belong to the large transforming growth factor-β (TGF-β) superfamily of multifunctional cytokines. BMP-2 can induce ectopic bone and cartilage formation in adult vertebrates and is involved in central steps in early embryonal development in animals. Signaling by these cytokines requires binding of two types of transmembrane serine/threonine receptor kinase chains classified as type I and type II. Here we report the crystal structure of human dimeric BMP-2 in complex with two high affinity BMP receptor IA extracellular domains (BRIAec). The receptor chains bind to the ‘wrist’ epitopes of the BMP-2 dimer and contact both BMP-2 monomers. No contacts exist between the receptor domains. The model reveals the structural basis for discrimination between type I and type II receptors and the variability of receptor–ligand interactions that is seen in BMP–TGF-β systems.
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References
Massagué, J. Annu. Rev. Biochem. 67, 753–791 (1998).
Liu, F., Ventura, F., Doody, J. & Massague, J. Mol. Cell. Biol. 15, 3479–3486 (1995).
ten Dijke, P. et al. J. Biol. Chem. 269, 16985–16988 (1994).
Mittl, P.R. et al. Protein Sci. 5, 1261–1271 (1996).
Scheufler, C., Sebald, W. & Hülsmeyer, M. J. Mol. Biol. 287, 103–115 (1999).
Hinck, A.P. et al. Biochemistry 35, 8517–8534 (1996).
Griffith, D.L., Keck, P.C., Sampath, T.K., Rueger, D.C. & Carlson, W.D. Proc. Natl. Acad. Sci. USA 93, 878–883 (1996).
Daopin, S., Piez, K.A., Ogawa, Y. & Davies, D.R. Science 257, 369–373 (1992).
Schlunegger, M.P. & Grutter, M.G. Nature 358, 430–434 (1992).
Eigenbrot, C. & Gerber, N. Nature Struct. Biol. 4, 435–438 (1997).
Greenwald, J., Fischer, W.H., Vale, W.W. & Choe, S. Nature Struct. Biol. 6, 18–22 (1999).
Rees, B. & Bilwes, A. Chem. Res. Toxicol. 6, 385–406 (1993).
Isaacs, N.W. Curr. Opin. Struct. Biol. 5, 391–395 (1995).
Wells, J.A. et al. Recent Prog. Horm. Res. 48, 253–275 (1993).
Hage, T., Sebald, W. & Reinemer, P. Cell 97, 271–281 (1999).
Huang, S.S., Zhou, M., Johnson, F.E., Shieh, H.S. & Huang, J.S. J. Biol. Chem. 274, 27754–27758 (1999).
Gray, P.C. et al. J. Biol. Chem. 275, 3206–3212 (2000).
Lux, A., Attisano, L. & Marchuk, D.A. J. Biol. Chem. 274, 9984–9992 (1999).
Wiesmann, C. et al. Cell 91, 695–704 (1997).
Wiesmann, C., Ultsch, M.H., Bass, S.H. & de Vos, A.M. Nature 401, 184–188 (1999).
Ruppert, R., Hoffmann, E. & Sebald, W. Eur. J. Biochem. 237, 295–302 (1996).
Kirsch, T., Nickel, J. & Sebald, W. FEBS Lett. 468, 215–219 (2000).
Kabsch, W. J. Appl. Crystallogr. 26, 795–800 (1993).
Collaborative Computational Project, Number 4. CCP4 Suite: programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994).
Brunger, A.T. et al. Acta Crystallogr. D 54, 905–921 (1998).
Jones, T.A., Zou, J.Y., Cowan, S.W. & Kjeldgaard, M. Acta Crystallogr. A 47, 110–119 (1991).
Carson, M. J. Applied Crystallogr. 24, 958–961 (1991).
Nicholls, A., Sharp, K.A. & Honig, B. Proteins 11, 281–296 (1991).
Corpet, F. Nucleic Acids Res. 16, 10881–10890 (1988).
Acknowledgements
We thank P. Knaus for critical reading of the manuscript and M. Gottermeier for technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 487).
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Kirsch, T., Sebald, W. & Dreyer, M. Crystal structure of the BMP-2–BRIA ectodomain complex. Nat Struct Mol Biol 7, 492–496 (2000). https://doi.org/10.1038/75903
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DOI: https://doi.org/10.1038/75903