Structure of bone morphogenetic protein 9 procomplex.
Publication Type:Journal Article
Source:Proc Natl Acad Sci U S A, Volume 112, Issue 12, p.3710-5 (2015)
Keywords:Amino Acid Sequence, Animals, Bone Morphogenetic Protein 7, CHO Cells, Cricetinae, Cricetulus, Growth Differentiation Factors, HEK293 Cells, Humans, Intercellular Signaling Peptides and Proteins, Molecular Sequence Data, Protein Structure, Secondary, Protein Structure, Tertiary, Sequence Homology, Amino Acid, Signal Transduction, Transforming Growth Factor beta
<p>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. </p>