Abstract
The interplay between bone morphogenetic proteins (BMPs) and their antagonists governs developmental and cellular processes as diverse as establishment of the embryonic dorsal–ventral axis, induction of neural tissue, formation of joints in the skeletal system and neurogenesis in the adult brain. So far, the three-dimensional structures of BMP antagonists and the structural basis for inactivation have remained unknown. Here we report the crystal structure of the antagonist Noggin bound to BMP-7, which shows that Noggin inhibits BMP signalling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors. The BMP-7-binding affinity of site-specific variants of Noggin is correlated with alterations in bone formation and apoptosis in chick limb development, showing that Noggin functions by sequestering its ligand in an inactive complex. The scaffold of Noggin contains a cystine (the oxidized form of cysteine) knot topology similar to that of BMPs; thus, ligand and antagonist seem to have evolved from a common ancestral gene.
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Acknowledgements
We thank Curis for BMP-7; Regeneron Pharmaceuticals for Noggin; K. Baban for technical assistance; M. Austin for aid with crystal/cryo-optimization; G. Louie for phasing advice; and the staff at SSRL for help with data collection. The SSRL Structural Molecular Biology Program is supported by the Department of Energy and the NIH. J. Groppe is grateful to K. Kirschner and T. Kiefhaber for their initial support. J. Greenwald acknowledges support from a National Cancer Institute Training Grant. This work was supported by grants from the Swiss National Science Foundation and the Kantons Basel (M.A.), BioCell, National Science Foundation, the G. Harold and Leila Y. Mathers Charitable Foundation, and the Fundacao Calouste Gulbenkian and Fundacao para Ciencia e Technologia (J.R.L., J.C.I.B.), and the National Institutes of Health (S.C., W.W.V.).
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Groppe, J., Greenwald, J., Wiater, E. et al. Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 420, 636–642 (2002). https://doi.org/10.1038/nature01245
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DOI: https://doi.org/10.1038/nature01245
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