Structural insights into conformational switching in latency-associated peptide between transforming growth factor β-1 bound and unbound states.
IUCRJ(2020)
摘要
Transforming growth factor beta-1 (TGF beta-1) is a secreted signalling protein that directs many cellular processes and is an attractive target for the treatment of several diseases. The primary endogenous activity regulatory mechanism for TGF beta-1 is sequestration by its pro-peptide, latency-associated peptide (LAP), which sterically prohibits receptor binding by caging TGF beta-1. As such, recombinant LAP is promising as a protein-based therapeutic for modulating TGF beta-1 activity; however, the mechanism of binding is incompletely understood. Comparison of the crystal structure of unbound LAP (solved here to 3.5 angstrom resolution) with that of the bound complex shows that LAP is in a more open and extended conformation when unbound to TGF beta-1. Analysis suggests a mechanism of binding TGF beta-1 through a large-scale conformational change that includes contraction of the inter-monomer interface and caging by the 'straight-jacket' domain that may occur in partnership through a loop-to-helix transition in the core jelly-roll fold. This conformational change does not appear to include a repositioning of the integrin-binding motif as previously proposed. X-ray scattering-based modelling supports this mechanism and reveals possible orientations and ensembles in solution. Although native LAP is heavily glycosylated, solution scattering experiments show that the overall folding and flexibility of unbound LAP are not influenced by glycan modification. The combination of crystallography, solution scattering and biochemical experiments reported here provide insight into the mechanism of LAP sequestration of TGF beta-1 that is of fundamental importance for therapeutic development.
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关键词
latency-associated peptide,transforming growth factor beta-1,growth factors,structural biology,TGF beta-1
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