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Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization

Author

Listed:
  • Christopher Agnew

    (University of California San Francisco)

  • Pelin Ayaz

    (D. E. Shaw Research)

  • Risa Kashima

    (University of California San Francisco)

  • Hanna S. Loving

    (Iowa State University)

  • Prajakta Ghatpande

    (University of California San Francisco)

  • Jennifer E. Kung

    (University of California San Francisco
    Genentech, Inc.)

  • Eric S. Underbakke

    (Iowa State University)

  • Yibing Shan

    (D. E. Shaw Research)

  • David E. Shaw

    (D. E. Shaw Research
    Columbia University)

  • Akiko Hata

    (University of California San Francisco
    University of California San Francisco)

  • Natalia Jura

    (University of California San Francisco
    University of California San Francisco)

Abstract

Upon ligand binding, bone morphogenetic protein (BMP) receptors form active tetrameric complexes, comprised of two type I and two type II receptors, which then transmit signals to SMAD proteins. The link between receptor tetramerization and the mechanism of kinase activation, however, has not been elucidated. Here, using hydrogen deuterium exchange mass spectrometry (HDX-MS), small angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations, combined with analysis of SMAD signaling, we show that the kinase domain of the type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes. Formation of this dimer is essential for ligand-induced receptor signaling and is targeted by mutations in BMPR2 in patients with pulmonary arterial hypertension (PAH). We further show that the type I/type II kinase domain heterodimer serves as the scaffold for assembly of the active tetrameric receptor complexes to enable phosphorylation of the GS domain and activation of SMADs.

Suggested Citation

  • Christopher Agnew & Pelin Ayaz & Risa Kashima & Hanna S. Loving & Prajakta Ghatpande & Jennifer E. Kung & Eric S. Underbakke & Yibing Shan & David E. Shaw & Akiko Hata & Natalia Jura, 2021. "Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25248-5
    DOI: 10.1038/s41467-021-25248-5
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    Cited by:

    1. Takenobu Katagiri & Sho Tsukamoto & Mai Kuratani & Shinnosuke Tsuji & Kensuke Nakamura & Satoshi Ohte & Yoshiro Kawaguchi & Kiyosumi Takaishi, 2023. "A blocking monoclonal antibody reveals dimerization of intracellular domains of ALK2 associated with genetic disorders," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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