Structures of TGF-β Receptor Complexes: Implications for Function and Therapeutic Intervention Using Ligand Traps

Andrew      P. Hinck; Maureen      D. O'Connor-McCourt

Abstract

TGF-β isoforms (TGF-β1, -β2, and -β3) are secreted signaling ligands that stimulate the expression of protein components of the extracellular matrix, regulate the growth and differentiation of epithelial cells, modulate immune cell function, and play roles in the development of several essential organs, including the heart and lungs. The importance of the TGF-βs is underscored by their conservation among vertebrates and by their demonstrated roles in a variety of human diseases, including tissue fibrosis and cancer. The objective of this review is to highlight recent progress in characterizing the structures of the three TGF-β isoforms in complex with their receptors, and to compare these with one another as well as with other members of the superfamily. Although the structural information and accompanying biophysical studies emphasize the shared ancestry of TGF-βs, they also provide insight as to how the TGF-βs diverged from other members of the superfamily and one another to fulfill distinct roles in vivo. The similarities and differences by which the isoforms bind their receptors present unique opportunities for designing pan-isoform and isoform-specific ligand traps and progress toward developing these is described.

Keywords: TGF-β, TβR-I, TβR-II, TβR-III, betaglycan, structure, three-dimensional, ligand traps, dimeric structure, TGF-β Superfamily Signaling, target genes, glycine-serine, epithelial cells, central β-sheet, crystal structure