Structural biology of betaglycan and endoglin, membrane-bound co-receptors of the TGF-beta family

Betaglycan and endoglin, membrane-bound co-receptors of the TGF-β family, are required to mediate the signaling of a select subset of TGF-β family ligands, TGF-β2 and InhA, and BMP-9 and BMP-10, respectively. Previous biochemical and biophysical methods suggested alternative modes of ligand binding might be responsible for these co-receptors to selectively recognize and potentiate the functions of their ligands, yet the molecular details were lacking. Recent progress determining structures of betaglycan and endoglin, both alone and as bound to their cognate ligands, is presented herein. The structures reveal relatively minor, but very significant structural differences that lead to entirely different modes of ligand binding. The different modes of binding nonetheless share certain commonalities, such as multivalency, which imparts the co-receptors with very high affinity for their cognate ligands, but at the same time provides a mechanism for release by stepwise binding of the signaling receptors, both of which are essential for their functions. Impact statement: The TGF-β family is one of the most highly diversified signaling families, with essential roles in nearly all aspects of metazoan biology. Though functionally diverse, all 33 human TGF-β family ligands signal through a much more limited number of receptors. Thus the signaling repertoire is limited and cannot account for the functional diversity of signaling ligands in vivo. This mini review covers recent advances in our understanding of the structural basis by which two co-receptors of the family, betaglycan and endoglin, selectively recognize a limited subset of TGF-β family ligands and enable their functions in the cells and tissues in which they are expressed. The advances described also highlight gaps in current understanding of how the co-receptors are displaced upon engagement by the signaling receptors and how they function in a physiological environment, and thus suggest new avenues for investigation that will further illuminate how these essential co-receptors function in vivo.