TGF-{beta}2 uses the concave surface of its extended finger region to bind betaglycan’s ZP domain via three residues specific to TGF-{beta} and Inhibin-{alpha} [Protein Structure and Folding]

Betaglycan (BG) is a membrane-bound co-receptor of the TGF-β family that selectively binds transforming growth factor-β (TGF-β) isoforms and inhibin A (InhA) to enable temporal-spatial patterns of signaling essential for their functions in vivo. Here, using NMR titrations of methyl-labeled TGF-β2 with BG's C-terminal binding domain, BGZP-C, and surface plasmon resonance binding measurements with TGF-β2 variants, we found that the BGZP-C binding site on TGF-β2 is located on the inner surface of its extended finger region. Included in this binding site are Ile92, Lys97, and Glu99, which are entirely or mostly specific to the TGF-β isoforms and the InhA α-subunit, but unconserved in other TGF-β family growth factors (GFs). In accord with the proposed specificity-determining role of these residues, BG bound bone morphogenetic protein 2 (BMP-2) weakly or not at all, and TGF-β2 variants with the corresponding residues from BMP-2 bound BGZP-C more weakly than corresponding alanine variants. The BGZP-C binding site on InhA previously was reported to be located on the outside of the extended finger region, yet at the same time, to include, Ser112 and Lys119, homologous to TGF-β2 Ile92 and Lys97, on the inside of the fingers. Therefore, it is likely that both TGF-β2 and InhA bind BGZP-C through a site on the inside of their extended finger regions. Overall, these results identify the BGZP-C–binding site on TGF-β2 and shed light on the specificity of BG for select TGF-β–type GFs and the mechanisms by which BG influences their signaling.

from ! Human Diseases via Alexandros G.Sfakianakis on Inoreader http://bit.ly/2EZLW6v