Structural Superimposition

Abstact

Transforming growth factor-beta (TGFbeta) is a potent cytokine that controls all aspects of cellular behavior. TGFbeta is secreted in complex with its prodomain and latent TGFbeta-binding protein-1 (LTBP1), forming the large latent complex (LLC), which through interaction with the extracellular matrix enables integrin-mediated activation. Although TGFbeta structures are known, the influence of LTBP1 on the structure and activity of TGFbeta is unknown. Here, we report the LLC cryo-EM structure comprising the LTBP1 eight-cysteine domain covalently bound to TGFbeta, revealing a hydrophobic interface between TGFbeta and LTBP1. Structure-guided mutagenesis shows that the interface is important for complex formation and TGFbeta activity. Our structure supports a contralateral domain swapped architecture in the LLC, and simulations show that this architecture requires increased force to overcome barriers for integrin-mediated activation, while the covalent attachment of TGFbeta to LTBP1 redistributes force to reduce unfolding barriers. These insights will be important for therapeutic strategies targeting TGFbeta.