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Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10

Author

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  • Jingxu Guo

    (University of Cambridge School of Clinical Medicine)

  • Bin Liu

    (University of Cambridge School of Clinical Medicine)

  • Midory Thorikay

    (Leiden University Medical Centre)

  • Minmin Yu

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

  • Xiaoyan Li

    (University of Cambridge School of Clinical Medicine)

  • Zhen Tong

    (University of Cambridge School of Clinical Medicine)

  • Richard M. Salmon

    (University of Cambridge School of Clinical Medicine)

  • Randy J. Read

    (The Keith Peters Building, Cambridge Biomedical Campus, Hills Road)

  • Peter ten Dijke

    (Leiden University Medical Centre)

  • Nicholas W. Morrell

    (University of Cambridge School of Clinical Medicine)

  • Wei Li

    (University of Cambridge School of Clinical Medicine)

Abstract

Heterozygous mutations in BMPR2 (bone morphogenetic protein (BMP) receptor type II) cause pulmonary arterial hypertension. BMPRII is a receptor for over 15 BMP ligands, but why BMPR2 mutations cause lung-specific pathology is unknown. To elucidate the molecular basis of BMP:BMPRII interactions, we report crystal structures of binary and ternary BMPRII receptor complexes with BMP10, which contain an ensemble of seven different BMP10:BMPRII 1:1 complexes. BMPRII binds BMP10 at the knuckle epitope, with the A-loop and β4 strand making BMPRII-specific interactions. The BMPRII binding surface on BMP10 is dynamic, and the affinity is weaker in the ternary complex than in the binary complex. Hydrophobic core and A-loop interactions are important in BMPRII-mediated signalling. Our data reveal how BMPRII is a low affinity receptor, implying that forming a signalling complex requires high concentrations of BMPRII, hence mutations will impact on tissues with highest BMPR2 expression such as the lung vasculature.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30111-2
    DOI: 10.1038/s41467-022-30111-2
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    References listed on IDEAS

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    1. 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.
    2. Stefan Gräf & Matthias Haimel & Marta Bleda & Charaka Hadinnapola & Laura Southgate & Wei Li & Joshua Hodgson & Bin Liu & Richard M. Salmon & Mark Southwood & Rajiv D. Machado & Jennifer M. Martin & C, 2018. "Identification of rare sequence variation underlying heritable pulmonary arterial hypertension," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
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