The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly.
Activins and bone morphogenetic proteins (BMPs) elicit diverse biological responses by signaling through two pairs of structurally related type I and type II receptors. Here we report the crystal structure of BMP7 in complex with the extracellular domain (ECD) of the activin type II receptor. Our structure produces a compelling four-receptor model, revealing that the types I and II receptor ECDs make no direct contacts. Nevertheless, we find that truncated receptors lacking their cytoplasmic domain retain the ability to cooperatively assemble in the cell membrane. Also, the affinity of BMP7 for its low-affinity type I receptor ECD increases 5-fold in the presence of its type II receptor ECD. Taken together, our results provide a view of the ligand-mediated cooperative assembly of BMP and activin receptors that does not rely on receptor-receptor contacts.
Greenwald
Jason
J
Structural Biology Laboratory, The Salk Institute, La Jolla, CA 92037, USA.
Groppe
Jay
J
Gray
Peter
P
Wiater
Ezra
E
Kwiatkowski
Witek
W
Vale
Wylie
W
Choe
Senyon
S
D030301:Activin Receptors, Type II / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000378:metabolism; D000939:Epitopes; D004926:Escherichia coli / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance; D016212:Transforming Growth Factor beta / Q000378:metabolism
C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D003432:Cross-Linking Reagents; D000939:Epitopes; D008024:Ligands; D016212:Transforming Growth Factor beta; D008156:Luciferases; D030301:Activin Receptors, Type II