Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms.
Beech, John S
Grainger, David J
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Salmon, R. M., Guo, J., Wood, J., Tong, Z., Beech, J. S., Lawera, A., Yu, M., et al. (2020). Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms.. Nature communications, 11 (1), 1621. https://doi.org/10.1038/s41467-020-15425-3
Activin receptor-like kinase 1 (ALK1)-mediated endothelial cell signalling in response to bone morphogenetic protein 9 (BMP9) and BMP10 is of significant importance in cardiovascular disease and cancer. However, detailed molecular mechanisms of ALK1-mediated signalling remain unclear. Here, we report crystal structures of the BMP10:ALK1 complex at 2.3 Å and the prodomain-bound BMP9:ALK1 complex at 3.3 Å. Structural analyses reveal a tripartite recognition mechanism that defines BMP9 and BMP10 specificity for ALK1, and predict that crossveinless 2 is not an inhibitor of BMP9, which is confirmed by experimental evidence. Validating the tripartite mechanism by introducing BMP10-specific residues into BMP9 has generated BMP10-like ligands with diminished signalling activity in C2C12 cells. Surprisingly, the loss of osteogenic signalling in C2C12 does not translate into non-osteogenic activity in vivo and BMP10 also induces bone-formation. Collectively, these comprehensive data provide essential insight into ALK1-mediated BMP9 and BMP10 signalling, facilitating therapeutic targeting of this important pathway.
Bone and Bones, Cell Line, Endothelial Cells, Animals, Mice, Inbred C57BL, Humans, Mice, Activin Receptors, Type II, Transforming Growth Factor beta, Bone Morphogenetic Proteins, Ligands, Crystallography, X-Ray, Signal Transduction, Binding Sites, Protein Conformation, Models, Molecular, Male, Growth Differentiation Factor 2, Protein Domains
British Heart Foundation
British Heart Foundation (PG/12/54/29734)
British Heart Foundation (PG/15/39/31519)
British Heart Foundation (PG/17/1/32532)
British Heart Foundation (PG/17/58/33134)
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External DOI: https://doi.org/10.1038/s41467-020-15425-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/303138
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