Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms

Richard M. Salmon, Jingxu Guo, Jennifer H. Wood, Zhen Tong, John S. Beech, Aleksandra Lawera, Minmin Yu, David J. Grainger, Jill Reckless, Nicholas W. Morrell and Wei Li ()
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Richard M. Salmon: University of Cambridge School of Clinical Medicine
Jingxu Guo: University of Cambridge School of Clinical Medicine
Jennifer H. Wood: University of Cambridge School of Clinical Medicine
Zhen Tong: University of Cambridge School of Clinical Medicine
John S. Beech: RxCelerate Ltd, Babraham Research Campus
Aleksandra Lawera: University of Cambridge School of Clinical Medicine
Minmin Yu: MRC Laboratory of Molecular Biology
David J. Grainger: RxCelerate Ltd, Babraham Research Campus
Jill Reckless: RxCelerate Ltd, Babraham Research Campus
Nicholas W. Morrell: University of Cambridge School of Clinical Medicine
Wei Li: University of Cambridge School of Clinical Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15425-3

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