Fig. 5: Model illustrating the inhibition of BMP signaling by TWSG1.

Dimeric BMP ligands assemble a complex that comprises two BMPR1 and two BMPR2 receptors to activate downstream signaling. The TWSG1 NTD occupies the BMPR1-binding site on BMP ligands and inhibits signaling by competing with BMPR1 for binding. The TWSG1 CTD interacts with members of the Chordin family, adding another layer to BMP–TWSG1 regulation. The dimeric nature of both the BMP ligand and TWSG1 (observed in structures and in solution) could lead to the oligomerization and clustering of the BMP–TWSG1 complex. Ternary signaling complexes were modeled based on the BMPR1A–BMP2–ActR2b structure (PDB ID 2H62)²⁴, as well as the TWSG1 apo and TWSG1–GDF5 structures (this study).