Ternary Complex of Transforming Growth Factor-[beta]1 Reveals Isoform-specific Ligand Recognition and Receptor Recruitment in the Superfamily
- Texas-HSC
Transforming growth factor (TGF)-{beta}1, -{beta}2, and -{beta}3 are 25-kDa homodimeric polypeptides that play crucial nonoverlapping 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{sup o} 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.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1002401
- Journal Information:
- J. Biol. Chem., Vol. 285, Issue (19) ; 05, 2010; ISSN 0021-9258
- Country of Publication:
- United States
- Language:
- ENGLISH
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