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Latent-TGF-β has a domain swapped architecture.
Mingliang Jin1, Robert I Seed2, Tiffany Shing2
1Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.
Nature Communications
|November 25, 2025
Summary
Transforming growth factor-beta (TGF-β) latency is maintained by its prodomain ring. This study reveals a domain-swapped architecture of latent TGF-β, clarifying its activation mechanism.
Area of Science:
- Molecular Biology
- Cell Signaling
- Protein Structure
Background:
- Transforming growth factor-beta (TGF-β) is a crucial cytokine involved in numerous cellular processes.
- TGF-β is secreted in a latent complex (L-TGF-β), where its prodomains keep the mature cytokine inactive.
- The precise structural organization of L-TGF-β, essential for its activation, remains incompletely understood.
Purpose of the Study:
- To elucidate the domain architecture of latent TGF-β (L-TGF-β).
- To address the gap in mechanistic understanding of L-TGF-β activation.
- To provide definitive experimental evidence for the structural basis of TGF-β latency.
Main Methods:
- Experimental determination of the L-TGF-β complex structure.
- Analysis of protein interactions and conformational changes.
- Structural biology techniques to visualize the domain arrangement.
Main Results:
- Demonstrated a definitive domain-swapped architecture for L-TGF-β.
- The revealed structure explains how the prodomain ring sterically hinders TGF-β receptor binding.
- Provides a structural basis for understanding how integrin binding can lead to L-TGF-β activation.
Conclusions:
- The study resolves the long-standing question regarding L-TGF-β domain architecture.
- Understanding this structure is critical for deciphering TGF-β signaling regulation.
- This finding opens new avenues for therapeutic strategies targeting TGF-β pathways.
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