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Structures of TGF-β with betaglycan and signaling receptors reveal mechanisms of complex assembly and signaling

Author

Listed:
  • Łukasz Wieteska

    (University of Pittsburgh
    University of Leeds
    The Francis Crick Institute)

  • Alexander B. Taylor

    (The University of Texas Health Science Center at San Antonio)

  • Emma Punch

    (The Francis Crick Institute)

  • Jonathan A. Coleman

    (University of Pittsburgh)

  • Isabella O. Conway

    (University of Pittsburgh)

  • Yeu-Farn Lin

    (McGill University)

  • Chang-Hyeock Byeon

    (University of Pittsburgh)

  • Cynthia S. Hinck

    (University of Pittsburgh)

  • Troy Krzysiak

    (University of Pittsburgh)

  • Rieko Ishima

    (University of Pittsburgh)

  • Fernando López-Casillas

    (UNAM)

  • Peter Cherepanov

    (The Francis Crick Institute)

  • Daniel J. Bernard

    (McGill University)

  • Caroline S. Hill

    (The Francis Crick Institute)

  • Andrew P. Hinck

    (University of Pittsburgh)

Abstract

Betaglycan (BG) is a transmembrane co-receptor of the transforming growth factor-β (TGF-β) family of signaling ligands. It is essential for embryonic development, tissue homeostasis and fertility in adults. It functions by enabling binding of the three TGF-β isoforms to their signaling receptors and is additionally required for inhibin A (InhA) activity. Despite its requirement for the functions of TGF-βs and InhA in vivo, structural information explaining BG ligand selectivity and its mechanism of action is lacking. Here, we determine the structure of TGF-β bound both to BG and the signaling receptors, TGFBR1 and TGFBR2. We identify key regions responsible for ligand engagement, which has revealed binding interfaces that differ from those described for the closely related co-receptor of the TGF-β family, endoglin, thus demonstrating remarkable evolutionary adaptation to enable ligand selectivity. Finally, we provide a structural explanation for the hand-off mechanism underlying TGF-β signal potentiation.

Suggested Citation

  • Łukasz Wieteska & Alexander B. Taylor & Emma Punch & Jonathan A. Coleman & Isabella O. Conway & Yeu-Farn Lin & Chang-Hyeock Byeon & Cynthia S. Hinck & Troy Krzysiak & Rieko Ishima & Fernando López-Cas, 2025. "Structures of TGF-β with betaglycan and signaling receptors reveal mechanisms of complex assembly and signaling," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56796-9
    DOI: 10.1038/s41467-025-56796-9
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    References listed on IDEAS

    as
    1. Jiahua He & Tao Li & Sheng-You Huang, 2023. "Improvement of cryo-EM maps by simultaneous local and non-local deep learning," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Minlong Shi & Jianghai Zhu & Rui Wang & Xing Chen & Lizhi Mi & Thomas Walz & Timothy A. Springer, 2011. "Latent TGF-β structure and activation," Nature, Nature, vol. 474(7351), pages 343-349, June.
    3. Monika Bokori-Brown & Thomas G. Martin & Claire E. Naylor & Ajit K. Basak & Richard W. Titball & Christos G. Savva, 2016. "Cryo-EM structure of lysenin pore elucidates membrane insertion by an aerolysin family protein," Nature Communications, Nature, vol. 7(1), pages 1-7, September.
    4. Kathy A. Lewis & Peter C. Gray & Amy L. Blount & Leigh A. MacConell & Ezra Wiater & Louise M. Bilezikjian & Wylie Vale, 2000. "Betaglycan binds inhibin and can mediate functional antagonism of activin signalling," Nature, Nature, vol. 404(6776), pages 411-414, March.
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