2016 January 19 | Minlong Shi, Jianghai Zhu, Rui Wang, Xing Chen, Lizhi Mi, Thomas Walz, and Timothy A. Springer
The article describes the structure of latent transforming growth factor (TGF)-β1 and its activation mechanism. TGF-β1 is stored in the extracellular matrix as a latent complex with its prodomain, which is activated by binding to αv integrins and force application. Crystals of dimeric porcine proTGF-β1 reveal a ring-shaped complex with a novel fold for the prodomain, showing how the prodomain shields the growth factor from receptors and alters its conformation. The structure indicates that complex formation between αvβ6 integrin and the prodomain is insufficient for TGF-β1 release. Force-dependent activation requires the unfastening of a 'straitjacket' that encircles each growth-factor monomer, which can be loosened by disulfide bond formation or mechanical force. The prodomain's structure is conserved across all 33 TGF-β family members, suggesting a similar mechanism of regulation. The findings provide insights into the regulation of a family of growth and differentiation factors crucial for morphogenesis and homeostasis.The article describes the structure of latent transforming growth factor (TGF)-β1 and its activation mechanism. TGF-β1 is stored in the extracellular matrix as a latent complex with its prodomain, which is activated by binding to αv integrins and force application. Crystals of dimeric porcine proTGF-β1 reveal a ring-shaped complex with a novel fold for the prodomain, showing how the prodomain shields the growth factor from receptors and alters its conformation. The structure indicates that complex formation between αvβ6 integrin and the prodomain is insufficient for TGF-β1 release. Force-dependent activation requires the unfastening of a 'straitjacket' that encircles each growth-factor monomer, which can be loosened by disulfide bond formation or mechanical force. The prodomain's structure is conserved across all 33 TGF-β family members, suggesting a similar mechanism of regulation. The findings provide insights into the regulation of a family of growth and differentiation factors crucial for morphogenesis and homeostasis.