Latent TGF-[beta] structure and activation
- Harvard-Med
Transforming growth factor (TGF)-{beta} is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-{beta}1 requires the binding of {alpha}v 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-{beta} binding proteins. Crystals of dimeric porcine proTGF-{beta}1 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 {alpha}v{beta}6 integrin and the prodomain is insufficient for TGF-{beta}1 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-{beta} 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.
- Research Organization:
- Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
- Sponsoring Organization:
- UNIVERSITYHHMI
- OSTI ID:
- 1020587
- Journal Information:
- Nature, Journal Name: Nature Journal Issue: 06, 2011 Vol. 474
- Country of Publication:
- United States
- Language:
- ENGLISH
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