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Latent-TGF-β has a domain swapped architecture
Stephen Nishimura1, Mingliang Jin2, Robert Seed2
1University of California, San Francisco.
Research Square
|November 22, 2024
Summary
Transforming growth factor-beta (TGF-b) is activated through a domain-swapped architecture in its latent form (L-TGF-b). This structure is key to the dynamic allostery mechanism required for TGF-b signaling.
Area of Science:
- Molecular Biology
- Cell Signaling
- Biochemistry
Background:
- Transforming growth factor-beta (TGF-b) is a crucial cytokine involved in numerous cellular processes.
- TGF-b is secreted in a latent form (L-TGF-b), requiring activation to become biologically active.
- The latent form features a prodomain that sequesters mature TGF-b, preventing receptor interaction.
Purpose of the Study:
- To elucidate the structural basis of L-TGF-b activation.
- To investigate the role of the prodomain architecture in TGF-b signaling.
- To provide critical evidence defining the domain-swapped nature of L-TGF-b.
Main Methods:
- Structural analysis of latent TGF-b.
- Biochemical assays to study protein interactions.
- Investigating the RGD motif's role in integrin binding and allosteric activation.
Main Results:
- Demonstrated a domain-swapped architecture within the L-TGF-b complex.
- Identified this domain-swapping as an essential component of the dynamic allostery mechanism.
- Provided evidence linking integrin binding to the RGD motif with L-TGF-b activation.
Conclusions:
- The domain-swapped architecture of L-TGF-b is critical for its activation mechanism.
- Understanding this structure provides insights into TGF-b signaling regulation.
- This finding advances knowledge of how latent cytokines are released to initiate cellular responses.
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