Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms
Wood, Jennifer H.
Beech, John S.
Grainger, David J.
Nature Publishing Group UK
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Salmon, R. M., Guo, J., Wood, J. H., 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)https://doi.org/10.1038/s41467-020-15425-3
Abstract: 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. Introduction of BMP10-specific residues into BMP9 yields BMP10-like ligands with diminished signalling activity in C2C12 cells, validating the tripartite mechanism. The loss of osteogenic signalling in C2C12 does not translate into non-osteogenic activity in vivo and BMP10 also induces bone-formation. Collectively, these data provide insight into ALK1-mediated BMP9 and BMP10 signalling, facilitating therapeutic targeting of this important pathway.
Article, /631/45/127/1219, /631/80/86/2368, /631/443/63, /631/535/1266, /145, /96/95, /82/103, /82/83, /82/80, /82/51, /96/1, /82/16, /82/29, /38/61, article
British Heart Foundation (BHF) (PG/12/54/29734, PG/17/1/32532, PG/15/39/31519)
External DOI: https://doi.org/10.1038/s41467-020-15425-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/319438