Structural Adaptation in Its Orphan Domain Engenders Betaglycan with an Alternate Mode of Growth Factor Binding Relative to Endoglin

Betaglycan (BG) and endoglin (ENG), homologous co-receptors of the TGF-β family, potentiate the signaling activity of TGF-β2 and inhibin A, and BMP-9 and BMP-10, respectively. BG exists as monomer and forms 1:1 growth factor (GF) complexes, while ENG exists as a dimer and forms 2:1 GF complexes. Herein, the structure of the BG orphan domain (BG_O) reveals an insertion that blocks the region that the endoglin orphan domain (ENG_O) uses to bind BMP-9, preventing it from binding in the same manner. Using binding studies with domain-deleted forms of TGF-β and BG_O, as well as small-angle X-ray scattering data, BG_O is shown to bind its cognate GF in an entirely different manner compared with ENG_O. The alternative interfaces likely engender BG and ENG with the ability to selectively bind and target their cognate GFs in a unique temporal-spatial manner, without interfering with one another or other TGF-β family GFs. Kim et al. determine the structure of the betaglycan orphan domain (BG_O) and show that the edge β strand that endoglin uses to bind its cognate growth factor is blocked by an insertion. Binding studies and SAXS show that BG_O binds its cognate growth factor differently compared with endoglin.