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

Authors :
Salmon RM
Guo J
Wood JH
Tong Z
Beech JS
Lawera A
Yu M
Grainger DJ
Reckless J
Morrell NW
Li W
Source :
Nature communications [Nat Commun] 2020 Apr 01; Vol. 11 (1), pp. 1621. Date of Electronic Publication: 2020 Apr 01.
Publication Year :
2020

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.

Details

Language :
English
ISSN :
2041-1723
Volume :
11
Issue :
1
Database :
MEDLINE
Journal :
Nature communications
Publication Type :
Academic Journal
Accession number :
32238803
Full Text :
https://doi.org/10.1038/s41467-020-15425-3