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

Jay Groppe, Jason Greenwald, Ezra Wiater, Joaquin Rodriguez-Leon, Aris N. Economides, Witek Kwiatkowski, Markus Affolter, Wylie W. Vale, Juan Carlos Izpisua Belmonte and Senyon Choe ()
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Jay Groppe: Structural Biology, Salk Institute
Jason Greenwald: Structural Biology, Salk Institute
Ezra Wiater: Peptide Biology, Salk Institute
Joaquin Rodriguez-Leon: Instituto Gulbenkian de Ciencia
Aris N. Economides: Regeneron Pharmaceuticals
Witek Kwiatkowski: Structural Biology, Salk Institute
Markus Affolter: Biozentrum
Wylie W. Vale: Peptide Biology, Salk Institute
Juan Carlos Izpisua Belmonte: Salk Institute
Senyon Choe: Structural Biology, Salk Institute

Nature, 2002, vol. 420, issue 6916, 636-642

Abstract: 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.

Date: 2002
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DOI: 10.1038/nature01245

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