Structural basis of BMP signalling inhibition by the cystine knot protein Noggin.
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.
Groppe
Jay
J
Structural Biology, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Greenwald
Jason
J
Wiater
Ezra
E
Rodriguez-Leon
Joaquin
J
Economides
Aris N
AN
Kwiatkowski
Witek
W
Affolter
Markus
M
Vale
Wylie W
WW
Izpisua Belmonte
Juan Carlos
JC
Choe
Senyon
S
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D055419:Bone Morphogenetic Protein 7; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002352:Carrier Proteins; D002642:Chick Embryo; D018360:Crystallography, X-Ray; D003553:Cystine / Q000032:analysis*; D006801:Humans; D008024:Ligands; D018878:Limb Buds / Q000187:drug effects / Q000196:embryology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism; D017978:Receptors, Growth Factor; D016415:Sequence Alignment; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein
D055419:Bone Morphogenetic Protein 7; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D003553:Cystine; D008024:Ligands; D011506:Proteins; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C525819:BMP7 protein, human