Structural insights into conformational switching in latency-associated peptide between TGF[beta]-1 bound and unbound states
Timothy R. Stachowski, Mary E. Snell, and Edward H. Snell [1]
Molecular Tour
In response to environmental changes, proteins are released from cells that act as messengers, which allows cells to communicate with one another and coordinate a physiologic response. Transforming growth factor beta-1 (TGFb-1) is a protein used to communicate information about when and how cells should proliferate and is particularly important in organizing embryonic tissue development. The fundamental way our cells regulate TGFb-1 activity is with a second protein, latency-associated peptide (LAP). LAP forms a complex with TGFb-1, tethering it to the outside surface of the cell. Several pathologies including cancer progression and immune suppression are driven by an overabundance of TGFb-1.
Because LAP binding reduces TGFb-1 activity, recombinant LAP is a promising novel therapeutic approach, however a detailed understanding of how LAP binds TGFb-1 is missing, which could reveal ways to improve the LAP-TGFb-1 interaction or develop other anti-TGFb-1 therapies. In a paper in IUCrJ, Stachowski et al. show that LAP adopts structurally distinct conformations between unbound and TGFb-1 bound states. This was revealed by comparing the X-ray crystal structure of LAP in the unbound state solved by Stachowski et al. with the crystal structure of LAP bound to TGFb-1 previously reported by Shi et al. 2011. This analysis combined with solution modelling showed that LAP transitions from an extended to compact conformation when binding TGFb-1, simulating a type of hugging motion where LAP embraces TGFb-1. Surprisingly, this conformational change includes rearranging two domains that are distant from one another and might be coordinated through the formation of an a-helix that is distant from the LAP-TGFb-1 interaction site. Together, these results provide new spatial details about the TGFb-1 binding mechanism, specifically how LAP reorients itself to develop the LAP-TGFb-1 interface. This insight is important as it provides new avenues to engineer and improve LAP as a therapeutic that are focused beyond just the interaction site.
References
- ↑ Stachowski TR, Snell ME, Snell EH. Structural insights into conformational switching in latency-associated peptide between transforming growth factor beta-1 bound and unbound states. IUCrJ. 2020 Feb 6;7(Pt 2):238-252. doi: 10.1107/S205225251901707X. eCollection, 2020 Mar 1. PMID:32148852 doi:http://dx.doi.org/10.1107/S205225251901707X
