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<p>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.</p>

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Structural basis for the contribution of latent TGFβ binding protein to TGFβ latency and activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • George R. Biggin,
  • Matthew Snee,
  • Yu-Bai Xiao,
  • Catherine Smedley,
  • Alan R. F. Godwin,
  • Rana Dajani,
  • Holly L. Birchenough,
  • Thomas A. Jowitt,
  • Mark A. Travis,
  • Alan M. Roseman,
  • Anna Tarakanova,
  • Clair Baldock

摘要

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.