The structure of latent TGF-β1 reveals a ring-shaped complex with a novel prodomain fold, which shields the growth factor from receptor recognition and alters its conformation. Activation requires force exerted by αv integrins, which unfasten a 'straitjacket' that encircles each growth-factor monomer. This process is facilitated by disulphide bonds and involves interactions with latent TGF binding proteins (LTBPs). The prodomain of TGF-β1 contains an RGD motif recognized by αv integrins, and mutations in this motif affect TGF-β1 function. The structure of proTGF-β1 shows that the prodomain is sufficient to confer latency and targets many family members for storage in the extracellular matrix. The prodomain also plays a role in the regulation of TGF-β family members, including their biosynthesis, secretion, and activation. The structure of proTGF-β1 provides insights into the regulation of a family of growth and differentiation factors important in morphogenesis and homeostasis. The study also highlights the importance of integrin-dependent activation of TGF-β1 and the role of the prodomain in this process. The findings have implications for understanding the regulation of TGF-β family members in various biological contexts, including disease and tissue development. The study also describes the crystal structure of proTGF-β1 and the mechanisms of its activation by integrins, as well as the implications for the regulation of bioactivity in the TGF-β family. The study provides a detailed understanding of the structure and function of the prodomain of TGF-β1 and its role in the activation of TGF-β family members. The findings have important implications for the development of therapeutic strategies targeting TGF-β family members.The structure of latent TGF-β1 reveals a ring-shaped complex with a novel prodomain fold, which shields the growth factor from receptor recognition and alters its conformation. Activation requires force exerted by αv integrins, which unfasten a 'straitjacket' that encircles each growth-factor monomer. This process is facilitated by disulphide bonds and involves interactions with latent TGF binding proteins (LTBPs). The prodomain of TGF-β1 contains an RGD motif recognized by αv integrins, and mutations in this motif affect TGF-β1 function. The structure of proTGF-β1 shows that the prodomain is sufficient to confer latency and targets many family members for storage in the extracellular matrix. The prodomain also plays a role in the regulation of TGF-β family members, including their biosynthesis, secretion, and activation. The structure of proTGF-β1 provides insights into the regulation of a family of growth and differentiation factors important in morphogenesis and homeostasis. The study also highlights the importance of integrin-dependent activation of TGF-β1 and the role of the prodomain in this process. The findings have implications for understanding the regulation of TGF-β family members in various biological contexts, including disease and tissue development. The study also describes the crystal structure of proTGF-β1 and the mechanisms of its activation by integrins, as well as the implications for the regulation of bioactivity in the TGF-β family. The study provides a detailed understanding of the structure and function of the prodomain of TGF-β1 and its role in the activation of TGF-β family members. The findings have important implications for the development of therapeutic strategies targeting TGF-β family members.