Transforming growth factor-β (TGF-β) is the prototype of a large family of structurally related cytokines that play key roles in maintaining cellular homeostasis by signaling through two classes of functionally distinct Ser/Thr kinase receptors, designated as type I and type II. TGF-β initiates receptor assembly by binding with high affinity to the type II receptor. Here, we present the 2.15 Å crystal structure of the extracellular ligand-binding domain of the human TGF-β type II receptor (ecTβR2) in complex with human TGF-β3. ecTβR2 interacts with homodimeric TGF-β3 by binding identical finger segments at opposite ends of the growth factor. Relative to the canonical 'closed' conformation previously observed in ligand structures across the superfamily, ecTβR2-bound TGF-β3 shows an altered arrangement of its monomeric subunits, designated the 'open' conformation. The mode of TGF-β3 binding shown by ecTβR2 is compatible with both ligand conformations. This, in addition to the predicted mode for TGF-β binding to the type I receptor ectodomain (ecTβR1), suggests an assembly mechanism in which ecTβR1 and ecTβR2 bind at adjacent positions on the ligand surface and directly contact each other via proteinprotein interactions.
ASJC Scopus subject areas
- Structural Biology