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Latent TGF-β structure and activation

Author

Listed:
  • Minlong Shi

    (Immune Disease Institute, Harvard Medical School)

  • Jianghai Zhu

    (Immune Disease Institute, Harvard Medical School)

  • Rui Wang

    (Immune Disease Institute, Harvard Medical School)

  • Xing Chen

    (Immune Disease Institute, Harvard Medical School)

  • Lizhi Mi

    (Immune Disease Institute, Harvard Medical School)

  • Thomas Walz

    (Harvard Medical School)

  • Timothy A. Springer

    (Immune Disease Institute, Harvard Medical School)

Abstract

Transforming growth factor (TGF)-β is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-β1 requires the binding of αv integrin to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-β binding proteins. Crystals of dimeric porcine proTGF-β1 reveal a ring-shaped complex, a novel fold for the prodomain, and show how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between αvβ6 integrin and the prodomain is insufficient for TGF-β1 release. Force-dependent activation requires unfastening of a ‘straitjacket’ that encircles each growth-factor monomer at a position that can be locked by a disulphide bond. Sequences of all 33 TGF-β family members indicate a similar prodomain fold. The structure provides insights into the regulation of a family of growth and differentiation factors of fundamental importance in morphogenesis and homeostasis.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:nature:v:474:y:2011:i:7351:d:10.1038_nature10152
    DOI: 10.1038/nature10152
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    Cited by:

    1. 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.

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