TGF-2 uses the concave surface of its extended finger region to bind betaglycan’s ZP domain via three residues specific to TGF- and inhibin-

Morkos A. Henen, Pardeep Mahlawat, Christian W Zwieb, Ravindra B. Kodali, Cynthia S. Hinck, Ramsey D. Hanna, Troy C. Krzysiak, Udayar Ilangovan, Kristin E. Cano, Garrett Hinck, Machell Vonberg, Megan McCabe, Andrew P. Hinck

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Abstract

Betaglycan (BG) is a membrane-bound co-receptor of the TGF- family that selectively binds transforming growth factor- (TGF-) 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-2 with BG’s C-terminal binding domain, BG ZP-C , and surface plasmon resonance binding measurements with TGF-2 variants, we found that the BG ZP-C – binding site on TGF-2 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- isoforms and the InhA -subunit, but they are unconserved in other TGF- 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-2 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-2 Ile-92 and Lys-97, on the inside of the fingers. Therefore, it is likely that both TGF-2 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-2 and shed light on the specificity of BG for select TGF-–type GFs and the mechanisms by which BG influences their signaling.

Original languageEnglish (US)
Pages (from-to)3065-3080
Number of pages16
JournalJournal of Biological Chemistry
Volume294
Issue number9
DOIs
StatePublished - Jan 1 2019

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Henen, M. A., Mahlawat, P., Zwieb, C. W., Kodali, R. B., Hinck, C. S., Hanna, R. D., Krzysiak, T. C., Ilangovan, U., Cano, K. E., Hinck, G., Vonberg, M., McCabe, M., & Hinck, A. P. (2019). TGF-2 uses the concave surface of its extended finger region to bind betaglycan’s ZP domain via three residues specific to TGF- and inhibin-. Journal of Biological Chemistry, 294(9), 3065-3080. https://doi.org/10.1074/jbc.RA118.005210