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Structural basis of BMP signalling inhibition by the cystine knot protein Noggin.

Nature | Dec 12, 2002

http://www.ncbi.nlm.nih.gov/pubmed/12478285

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.

Pubmed ID: 12478285 RIS Download

Mesh terms: Amino Acid Sequence | Animals | Apoptosis | Bone Morphogenetic Protein 7 | Bone Morphogenetic Protein Receptors | Bone Morphogenetic Proteins | Carrier Proteins | Chick Embryo | Crystallography, X-Ray | Cystine | Humans | Ligands | Limb Buds | Models, Molecular | Molecular Sequence Data | Mutation | Protein Binding | Protein Conformation | Proteins | Receptors, Cell Surface | Receptors, Growth Factor | Sequence Alignment | Signal Transduction | Transforming Growth Factor beta

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