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Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms.
- 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.
- Subjects :
- Activin Receptors, Type II chemistry
Animals
Binding Sites
Bone Morphogenetic Proteins chemistry
Bone and Bones chemistry
Bone and Bones metabolism
Cell Line
Crystallography, X-Ray
Endothelial Cells metabolism
Growth Differentiation Factor 2 chemistry
Humans
Ligands
Male
Mice
Mice, Inbred C57BL
Models, Molecular
Protein Conformation
Protein Domains
Transforming Growth Factor beta metabolism
Activin Receptors, Type II metabolism
Bone Morphogenetic Proteins metabolism
Growth Differentiation Factor 2 metabolism
Signal Transduction physiology
Subjects
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