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

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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)

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.

Suggested Citation

  • 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 & Wei Li, 2020. "Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15425-3
    DOI: 10.1038/s41467-020-15425-3
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    Cited by:

    1. Jingxu Guo & Bin Liu & Midory Thorikay & Minmin Yu & Xiaoyan Li & Zhen Tong & Richard M. Salmon & Randy J. Read & Peter ten Dijke & Nicholas W. Morrell & Wei Li, 2022. "Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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