Latent TGF-β structure and activation

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. Members of the transforming growth factor-β (TGF-β) superfamily of growth factors are of fundamental importance in development and tissue homeostasis. TGF-β is secreted as an inactive complex that has to be activated to enable receptor binding and activation of downstream signalling events. Cell surface adhesion receptors of the integrin family are essential for the activation of TGF-β. Shi et al. present the structure of latent TGF-β and provide mechanistic insights into latency and force-dependent activation by integrins.