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 (BGO) reveals an insertion that blocks the region that the endoglin orphan domain (ENGO) uses to bind BMP-9, preventing it from binding in the same manner. Using binding studies with domain-deleted forms of TGF-β and BGO, as well as small-angle X-ray scattering data, BGO is shown to bind its cognate GF in an entirely different manner compared with ENGO. 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. [Display omitted] •Structure of the betaglycan orphan domain (BGO) was determined by crystallography•Structure reveals an insertion compared with the endoglin orphan domain (ENGO)•Insertion blocks the edge β strand used in the ENGO to bind BMP-9 or BMP-10•BGO binds TGF-β in a different manner than ENGO binds BMP-9 or BMP-10 Kim et al. determine the structure of the betaglycan orphan domain (BGO) 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 BGO binds its cognate growth factor differently compared with endoglin.