Crystal structure of BMP-9 and functional interactions with pro-region and receptors.
Bone morphogenetic proteins (BMPs), a subset of the transforming growth factor (TGF)-beta superfamily, regulate a diverse array of cellular functions during development and in the adult. BMP-9 (also known as growth and differentiation factor (GDF)-2) potently induces osteogenesis and chondrogenesis, has been implicated in the differentiation of cholinergic neurons, and may help regulate glucose metabolism. We have determined the structure of BMP-9 to 2.3 A and examined the differences between our model and existing crystal structures of other BMPs, both in isolation and in complex with their receptors. TGF-beta ligands are translated as precursors, with pro-regions that generally dissociate after cleavage from the ligand, but in some cases (including GDF-8 and TGF-beta1, -2, and -3), the pro-region remains associated after secretion from the cell and inhibits binding of the ligand to its receptor. Although the proregion of BMP-9 remains tightly associated after secretion, we find, in several cell-based assays, that the activities of BMP-9 and BMP-9.pro-region complex were equivalent. Activin receptor-like kinase 1 (ALK-1), an orphan receptor in the TGF-beta family, was also identified as a potential receptor for BMP-9 based on surface plasmon resonance studies (BIAcore) and the ability of soluble ALK-1 to block the activity of BMP-9.pro-region complex in cell-based assays.
Brown
Monica A
MA
Structural Biology Laboratory, The Salk Institute, La Jolla, California 92037, USA.
Zhao
Qinghai
Q
Baker
Kent A
KA
Naik
Chethana
C
Chen
Cecil
C
Pukac
Laurie
L
Singh
Mallika
M
Tsareva
Tatiana
T
Parice
Yanick
Y
Mahoney
Angela
A
Roschke
Viktor
V
Sanyal
Indra
I
Choe
Senyon
S
D041721:3T3-L1 Cells; D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II; D000469:Alkaline Phosphatase / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020219:Chondrogenesis; D002845:Chromatography; D018360:Crystallography, X-Ray / Q000379:methods*; D004591:Electrophoresis, Polyacrylamide Gel; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism; D055427:Growth Differentiation Factor 2; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D055435:Myostatin; D009474:Neurons / Q000378:metabolism; D010012:Osteogenesis; D011485:Protein Binding; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D016212:Transforming Growth Factor beta / Q000378:metabolism
C525719:Bmp2 protein, mouse; C525720:Bmp2 protein, rat; C525817:Bmp6 protein, mouse; C525818:Bmp6 protein, rat; C525821:Bmp7 protein, rat; D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D008024:Ligands; C525912:Mstn protein, mouse; C525913:Mstn protein, rat; D055435:Myostatin; D016212:Transforming Growth Factor beta; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse; D000469:Alkaline Phosphatase; D005947:Glucose