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Updated: Aug 7, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Structural basis for the contribution of latent TGFβ binding protein to TGFβ latency and activation
George R Biggin1,2, Matthew Snee1,2, Yu-Bai Xiao3
1Manchester Cell Matrix Centre, University of Manchester, Manchester, UK.
Abstract:
Transforming growth factor-β (TGFβ) is a potent cytokine that controls all aspects of cellular behavior. TGFβ is secreted in complex with its prodomain and latent TGFβ-binding protein-1 (LTBP1), forming the large latent complex (LLC), which through interaction with the extracellular matrix enables integrin-mediated activation. Although TGFβ structures are known, the influence of LTBP1 on the structure and activity of TGFβ is unknown. Here, we report the LLC cryo-EM structure comprising the LTBP1 eight-cysteine domain covalently bound to TGFβ, revealing a hydrophobic interface between TGFβ and LTBP1. Structure-guided mutagenesis shows that the interface is important for complex formation and TGFβ 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 TGFβ to LTBP1 redistributes force to reduce unfolding barriers. These insights will be important for therapeutic strategies targeting TGFβ.
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