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

Abstract

Betaglycan (BG) and endoglin (ENG), homologous co-receptors of the TGF-b family, potentiate the signaling activity of TGF-b2 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-b 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-b family GFs.

A bioinformatic analysis of the inhibin-betaglycan-endoglin/CD105 network reveals prognostic value in multiple solid tumors

“…INHA , TGFBR3 , and ENG impact patient outcomes more broadly and more significantly that INHBB and INHBA . There is also direct functional dependency of TGFBR3 and ENG to inhibin rather than activin [ 38 , 132 ]. We thus examined signatures associated with either a negative or positive outcome for each of the three genes.…”

“…Prior functional studies indicate a dependency on ENG and TGFBR3 for inhibin responsiveness [ 38 , 132 ]. To test if these biological observations hold in patient datasets, we performed supervised clustering using Euclidean algorithm of genes correlating with either INHA , ENG or TGFBR3 using the RNA-seq data for cancer types with the most significant impact as determined in Fig 6a .…”

“…Prior functional studies indicate a dependency on ENG and TGFBR3 for inhibin responsiveness [38,132]. To test if these biological observations hold in patient datasets, we performed supervised clustering using Euclidean algorithm of genes correlating with either INHA, ENG or TGFBR3 using the RNA-seq data for cancer types with the most significant impact as We find that INHA and TGFBR3 comparison rendered 1,430 genes, in which 24.6% were exclusive to INHA (e.g., DLL3, GPC2, TAZ, TERT, XYLT2) 37.7% to TGFBR3 (e.g., CCL2, CCR4, EGFR, GLCE, IL10RA, IL7R, ITGA1, ITGA2, JAK1, JAK2, SRGN, SULF1, TGFBR2), and 13.1% were positively correlated to both (e.g., CSPG4, COL4A3, FGF18, NOTCH4, SMAD9).…”

Structural perspective of BMP ligands and signaling

“…From this structure, a model of ENG binding to BMP9 was built including the proximal ZP domain, to highlight the symmetrical 2:1 ENG:ligand dimer complex (Fig 2D). This is in contrast to BG which binds ligands in a 1:1 stoichiometry, partially blocking the type I receptor binding site [107][108][109]. In general, ENG competes for the type II receptor epitope while allowing type I receptor binding [37].…”

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

“…One structurally minor, but potentially engage TGF-b2 dimers with high affinity. 70 On the basis of these observations, together with small angle X-ray scattering data which provides low-resolution structural information, models were constructed of the TGF-b:TbRII:orphan domain complex. One of the models that best fit these constraints is shown in Figure 7(d), and as shown, the orphan domain is nestled around the dimer, but in a manner that does not interfere with binding of either molecule of TbRII.…”