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Molecular recognition of BMP-2 and BMP receptor IA

Nature Structural & Molecular Biology volume 11, pages 481–488 (2004)Cite this article

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Abstract

Bone morphogenetic protein-2 (BMP-2) and other members of the TGF-β superfamily regulate the development, maintenance and regeneration of tissues and organs. Binding epitopes for these extracellular signaling proteins have been defined, but hot spots specifying binding affinity and specificity have so far not been identified. In this study, mutational and structural analyses show that epitopes of BMP-2 and the BRIA receptor form a new type of protein-protein interface. The main chain atoms of Leu 51 and Asp53 of BMP-2 represent a hot spot of binding to BRIA. The BMP-2 variant L51P was deficient in type I receptor binding only, whereas its overall structure and its binding to type II receptors and modulator proteins, such as noggin, were unchanged. Thus, the L51P substitution converts BMP-2 into a receptor-inactive inhibitor of noggin. These results are relevant for other proteins of the TGF-β superfamily and provide useful clues for structure-based drug design.

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Figure 1: Architecture of the interaction of BMP-2 and BRIA.
Figure 2: Central hydrogen-bonding network in the interface of BMP-2 and BRIA.
Figure 3: Comparison of BMP-2 bound to BRIA and BMP-2 L51P.
Figure 4: Biological activity of BMP-2 proline variants.
Figure 5: Neutralization of noggin inhibition by BMP-2 proline variant L51P.

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  • 11 April 2004

    Replaces Supp Table 1 file, added note to full text after SI note and on Supp Info index page

Notes

  1. *Note:The original Supplementary Table 1 contained symbol conversion errors and has been replaced with a new file.

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Acknowledgements

We thank M. Gottermeier and C. Söder for excellent technical assistance; M. Klein for help during data acquisition; M. Buehner for helpful discussions and advice; and D. Heinz and W. Schubert (Gesellschaft für Biotechnologische Forschung, GbF Braunschweig) for providing access to their X-ray diffraction equipment. The authors also thank C. Schulze-Briese and T. Tomizaki from Swiss Light Source for assistance during data acquisition and would like to acknowledge their access to the synchrotron radiation beamline X06SA at the Swiss Light Source (SLS), Switzerland. This project was supported by the Deutsche Forschungsgemeinschaft (DFG), SFB 487 TP B1 and B2.

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  1. Lehrstuhl für Physiologische Chemie II, Theodor-Boveri Institut für Biowissenschaften (Biozentrum) der Universität Würzburg, Am Hubland, Würzburg, D-97074, Germany

    Sascha Keller, Joachim Nickel, Jin-Li Zhang, Walter Sebald & Thomas D Mueller

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Correspondence to Thomas D Mueller.

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Supplementary information

Supplementary Fig. 1 (PDF 99 kb)

Supplementary Fig. 2 (PDF 20 kb)

Supplementary Table 1

*Note:The original Supplementary Table 1 contained symbol conversion errors and has been replaced with a new file. (PDF 125 kb)

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Keller, S., Nickel, J., Zhang, JL. et al. Molecular recognition of BMP-2 and BMP receptor IA. Nat Struct Mol Biol 11, 481–488 (2004). https://doi.org/10.1038/nsmb756

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