Journal:IUCrJ:S205225251901707X
From Proteopedia
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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 (TGFβ-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 TGFβ-1 activity is with a second protein, latency-associated peptide (LAP). LAP forms a complex with TGFβ-1, tethering it to the outside surface of the cell. Several pathologies including cancer progression and immune suppression are driven by an overabundance of TGFβ-1. | 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 (TGFβ-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 TGFβ-1 activity is with a second protein, latency-associated peptide (LAP). LAP forms a complex with TGFβ-1, tethering it to the outside surface of the cell. Several pathologies including cancer progression and immune suppression are driven by an overabundance of TGFβ-1. | ||
| - | Because LAP binding reduces TGFβ-1 activity, recombinant LAP is a promising novel therapeutic approach, however a detailed understanding of how LAP binds TGFβ-1 is missing, which could reveal ways to improve the LAP-TGFβ-1 interaction or develop other anti-TGFβ-1 therapies. In a paper in IUCrJ, ''Stachowski et al.'' show that LAP adopts structurally distinct conformations between unbound and TGFβ-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 TGFβ-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 TGFβ-1, simulating a type of hugging motion where LAP embraces TGFβ-1. Surprisingly, this conformational change includes rearranging two domains that are distant from one another and might be coordinated through the formation of an α-helix that is distant from the LAP-TGFβ-1 interaction site. Together, these results provide new spatial details about the TGFβ-1 binding mechanism, specifically how LAP reorients itself to develop the LAP-TGFβ-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. | + | Because LAP binding reduces TGFβ-1 activity, recombinant LAP is a promising novel therapeutic approach, however a detailed understanding of how LAP binds TGFβ-1 is missing, which could reveal ways to improve the LAP-TGFβ-1 interaction or develop other anti-TGFβ-1 therapies. In a paper in IUCrJ, ''Stachowski et al.'' show that LAP adopts structurally distinct conformations between unbound and TGFβ-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 TGFβ-1 previously reported by ''Shi et al.'' 2011 <ref name="Shi">PMID:21677751</ref>. This analysis combined with solution modelling showed that LAP transitions from an extended to compact conformation when binding TGFβ-1, simulating a type of hugging motion where LAP embraces TGFβ-1. Surprisingly, this conformational change includes rearranging two domains that are distant from one another and might be coordinated through the formation of an α-helix that is distant from the LAP-TGFβ-1 interaction site. Together, these results provide new spatial details about the TGFβ-1 binding mechanism, specifically how LAP reorients itself to develop the LAP-TGFβ-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. |
<b>References</b><br> | <b>References</b><br> | ||
Revision as of 08:50, 5 January 2020
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This page complements a publication in scientific journals and is one of the Proteopedia's Interactive 3D Complement pages. For aditional details please see I3DC.
