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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Guo, Jingxu 
Wood, Jennifer H 
Beech, John S 

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.

Description

Keywords

Activin Receptors, Type II, Animals, Binding Sites, Bone Morphogenetic Proteins, Bone and Bones, Cell Line, Crystallography, X-Ray, Endothelial Cells, Growth Differentiation Factor 2, Humans, Ligands, Male, Mice, Mice, Inbred C57BL, Models, Molecular, Protein Conformation, Protein Domains, Signal Transduction, Transforming Growth Factor beta

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

11

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
British Heart Foundation (None)
British Heart Foundation (PG/15/39/31519)
British Heart Foundation (PG/17/1/32532)
British Heart Foundation (PG/17/58/33134)
British Heart Foundation (None)
British Heart Foundation (FS/19/9/34146)
British Heart Foundation (RG/19/3/34265)
British Heart Foundation