LTBP isoforms differentially encode TGF-β spatial localization and activation

Wang, L.; Zhou, D.; Tan, J.; Lin, X.; Zhao, X.; Yuan, P.; Liu, J.; Li, R.; Wang, N.; Wang, Z.; Tian, F.-Y.; Li, Y.; Zhang, Z.; Zhao, B.

doi:10.64898/2026.08.05.743009

bioRxiv · 10.64898/2026.08.05.743009

LTBP isoforms differentially encode TGF-β spatial localization and activation

Wang, L.·Zhou, D.·Tan, J.·Lin, X.·Zhao, X.·Yuan, P.·Liu, J.·Li, R.·Wang, N.·Wang, Z.·Tian, F.-Y.·Li, Y.·Zhang, Z.·Zhao, B.

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Abstract

TGF-{beta} signals through a conserved pathway yet produces diverse outcomes, pointing to regulatory mechanisms upstream of receptor engagement. A family of four latent TGF-{beta} binding proteins (LTBPs) tether pro-TGF-{beta}s and control their localization and activation, but how distinct LTBPs contribute to this regulation is unclear. Here we combine cryo-electron microscopy with functional assays to dissect LTBP-pro-TGF-{beta} interactions. We resolve the LTBP-1/pro-TGF-{beta}1 and LTBP-3/pro-TGF-{beta}3 complex structures, revealing a conserved yet plastic hydrophobic binding interface, and systematically map key residues across all four LTBP and three pro-TGF-{beta} subtypes that determine binding specificity and affinity. Unexpectedly, LTBP-2, previously thought incapable of TGF-{beta} binding, engages pro-TGF-{beta}1 through a covalent linkage via its 16th EGF-like domain, providing a mechanistic link between LTBP-2 function and TGF-{beta} signaling. Beyond tethering, LTBP-3 shifts pro-TGF-{beta}3 from spontaneous activation toward integrin dependence, establishing LTPBs as dynamic modulators that dictate not only where but also how TGF-{beta} is unleashed. Collectively, these findings establish that LTBPs are not redundant ECM scaffolds but a family of functionally distinct regulators that differentially encode TGF-{beta} spatial localization and activation, with implications for isoform-selective therapeutic strategies.

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Wang, L., Zhou, D., Tan, J., Lin, X., Zhao, X., Yuan, P., Liu, J., Li, R., Wang, N., Wang, Z., Tian, F.-Y., Li, Y., Zhang, Z., Zhao, B.. 2026-08-06. LTBP isoforms differentially encode TGF-β spatial localization and activation. https://doi.org/10.64898/2026.08.05.743009

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