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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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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Inhibins
Transforming Growth Factors
Fingers
Binding Sites
Bone Morphogenetic Protein 2
betaglycan
Intercellular Signaling Peptides and Proteins
Protein Isoforms
Surface Plasmon Resonance
Surface plasmon resonance
Titration
Alanine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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

In: Journal of Biological Chemistry, Vol. 294, No. 9, 01.01.2019, p. 3065-3080.

Research output: Contribution to journalArticle

Henen, MA, Mahlawat, P, Zwieb, CW, Kodali, RB, Hinck, CS, Hanna, RD, Krzysiak, TC, Ilangovan, U, Cano, KE, Hinck, G, Vonberg, M, McCabe, M & Hinck, AP 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, vol. 294, no. 9, pp. 3065-3080. https://doi.org/10.1074/jbc.RA118.005210
Henen, Morkos A. ; Mahlawat, Pardeep ; Zwieb, Christian W ; Kodali, Ravindra B. ; Hinck, Cynthia S. ; Hanna, Ramsey D. ; Krzysiak, Troy C. ; Ilangovan, Udayar ; Cano, Kristin E. ; Hinck, Garrett ; Vonberg, Machell ; McCabe, Megan ; Hinck, Andrew P. / 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-. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 9. pp. 3065-3080.
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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.",
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T1 - 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-

AU - Henen, Morkos A.

AU - Mahlawat, Pardeep

AU - Zwieb, Christian W

AU - Kodali, Ravindra B.

AU - Hinck, Cynthia S.

AU - Hanna, Ramsey D.

AU - Krzysiak, Troy C.

AU - Ilangovan, Udayar

AU - Cano, Kristin E.

AU - Hinck, Garrett

AU - Vonberg, Machell

AU - McCabe, Megan

AU - Hinck, Andrew P.

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