Latent-TGF-β has a domain swapped architecture

Mingliang Jin, Robert I. Seed, Tiffany Shing, Li Wang, Junrui Li, Yifan Cheng () and Stephen L. Nishimura ()
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Mingliang Jin: University of California San Francisco, Department of Biochemistry and Biophysics
Robert I. Seed: University of California San Francisco, Department of Pathology
Tiffany Shing: University of California San Francisco, Department of Pathology
Li Wang: University of California San Francisco, Department of Pathology
Junrui Li: University of California San Francisco, Howard Hughes Medical Institute
Yifan Cheng: University of California San Francisco, Department of Biochemistry and Biophysics
Stephen L. Nishimura: University of California San Francisco, Department of Pathology

Nature Communications, 2025, vol. 16, issue 1, 1-9

Abstract: Abstract The multifunctional cytokine TGF-β is a dimeric protein produced within a latent complex (L-TGF-β). Latency is maintained by disulfide linked homodimeric prodomains forming a ring encircling the non-covalently bound mature TGF-β homodimer. This configuration sterically inhibits mature TGF-β from binding to its receptors. For TGF-β to be activated and bind to its receptors it must either be released, or if not released, overcome steric hinderance within the latent complex. Integrin binding to L-TGF-β results in activation with or without release of TGF-β by deforming the ring through different yet incompletely understood mechanisms. The domain architecture of L-TGF-β, which is not clearly defined, is a gap in mechanistic understanding of L-TGF-β activation. Here we fill this critical gap-in-knowledge by definitive experimental evidence demonstrating a domain-swapped architecture of L-TGF-β.

Date: 2025
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DOI: 10.1038/s41467-025-65465-w

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