Ternary Complex of Transforming Growth Factor-β1 Reveals Isoform-specific Ligand Recognition and Receptor Recruitment in the Superfamily

Transforming growth factor (TGF)-beta 1, -beta 2, and -beta 3 are 25-kDa homodimeric polypeptides that play crucial nonover-lapping roles in embryogenesis, tissue development, carcinogenesis, and immune regulation. Here we report the 3.0-angstrom resolution crystal structure of the ternary complex between human TGF-beta 1 and the extracellular domains of its type I and type II receptors, T beta RI and T beta RII. The TGF-beta 1 ternary complex structure is similar to previously reported TGF-beta 3 complex except with a 10 degrees rotation in T beta RI docking orientation. Quantitative binding studies showed distinct kinetics between the receptors and the isoforms of TGF-beta. T beta RI showed significant binding to TGF-beta 2 and TGF-beta 3 but not TGF-beta 1, and the binding to all three isoforms of TGF-beta was enhanced considerably in the presence of T beta RII. The preference of TGF-beta 2 to T beta RI suggests a variation in its receptor recruitment in vivo. Although TGF-beta 1 and TGF-beta 3 bind and assemble their ternary complexes in a similar manner, their structural differences together with differences in the affinities and kinetics of their receptor binding may underlie their unique biological activities. Structural comparisons revealed that the receptor-ligand pairing in the TGF-beta superfamily is dictated by unique insertions, deletions, and disulfide bonds rather than amino acid conservation at the interface. The binding mode of T beta RII on TGF-beta is unique to TGF-beta s, whereas that of type II receptor for bone morphogenetic protein on bone morphogenetic protein appears common to all other cytokines in the superfamily. Further, extensive hydrogen bonds and salt bridges are present at the high affinity cytokine-receptor interfaces, whereas hydrophobic interactions dominate the low affinity receptor-ligand interfaces.