TGF-β2 uses the concave surface of its extended finger region to bind betaglycan’s ZP domain via three residues specific to TGF-β and inhibin-α
| Autor: | Megan McCabe, Ravindra Kodali, Andrew P. Hinck, Christian W Zwieb, Kristin E. Cano, Pardeep Mahlawat, Morkos A. Henen, Machell Vonberg, Troy C. Krzysiak, Ramsey D. Hanna, Udayar Ilangovan, Garrett Hinck, Cynthia S. Hinck |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular 0301 basic medicine Gene isoform Biochemistry Bone morphogenetic protein 2 Protein Structure Secondary Substrate Specificity Mice Transforming Growth Factor beta2 03 medical and health sciences Protein Domains Cell surface receptor Animals Humans Inhibins Amino Acid Sequence Binding site Molecular Biology Alanine Binding Sites 030102 biochemistry & molecular biology INHA Chemistry Cell Biology Hydrogen-Ion Concentration Rats Cell biology A-site 030104 developmental biology Proteoglycans Receptors Transforming Growth Factor beta Protein Binding Signal Transduction Binding domain |
| Zdroj: | Journal of Biological Chemistry. 294:3065-3080 |
| ISSN: | 0021-9258 |
| Popis: | 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, BG(ZP-C), and surface plasmon resonance binding measurements with TGF-β2 variants, we found that the BG(ZP-C)–binding site on TGF-β2 is located on the inner surface of its extended finger region. Included in this binding site are Ile-92, Lys-97, and Glu-99, which are entirely or mostly specific to the TGF-β isoforms and the InhA α-subunit, but they are 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 BG(ZP-C) more weakly than corresponding alanine variants. The BG(ZP-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 Ser-112 and Lys-119, homologous to TGF-β2 Ile-92 and Lys-97, on the inside of the fingers. Therefore, it is likely that both TGF-β2 and InhA bind BG(ZP-C) through a site on the inside of their extended finger regions. Overall, these results identify the BG(ZP-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. |
| Databáze: | OpenAIRE |
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