Structure of bone morphogenetic protein 9 procomplex.
Bone morphogenetic proteins (BMPs) belong to the TGF-β family, whose 33 members regulate multiple aspects of morphogenesis. TGF-β family members are secreted as procomplexes containing a small growth factor dimer associated with two larger prodomains. As isolated procomplexes, some members are latent, whereas most are active; what determines these differences is unknown. Here, studies on pro-BMP structures and binding to receptors lead to insights into mechanisms that regulate latency in the TGF-β family and into the functions of their highly divergent prodomains. The observed open-armed, nonlatent conformation of pro-BMP9 and pro-BMP7 contrasts with the cross-armed, latent conformation of pro-TGF-β1. Despite markedly different arm orientations in pro-BMP and pro-TGF-β, the arm domain of the prodomain can similarly associate with the growth factor, whereas prodomain elements N- and C-terminal to the arm associate differently with the growth factor and may compete with one another to regulate latency and stepwise displacement by type I and II receptors. Sequence conservation suggests that pro-BMP9 can adopt both cross-armed and open-armed conformations. We propose that interactors in the matrix stabilize a cross-armed pro-BMP conformation and regulate transition between cross-armed, latent and open-armed, nonlatent pro-BMP conformations.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115; Department of Molecular and Structural Biology, School of Life Sciences, Tianjin University, Tianjin 300072, China;
Li-Zhi
LZ
Mi
Global BioTherapeutics Technologies, Pfizer Worldwide Research and Development, Cambridge, MA 02139; and.
Christopher T
CT
Brown
Global BioTherapeutics Technologies, Pfizer Worldwide Research and Development, Cambridge, MA 02139; and.
Yijie
Y
Gao
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115;
Yuan
Y
Tian
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115;
Viet Q
VQ
Le
Howard Hughes Medical Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Thomas
T
Walz
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115; timothy.springer@childrens.harvard.edu.
Timothy A
TA
Springer
D000595:Amino Acid Sequence; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000737:chemistry*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000737:chemistry*
C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D036341:Intercellular Signaling Peptides and Proteins; D016212:Transforming Growth Factor beta