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: Henen MA; From the Departments of Structural Biology and.; the Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900., Mahlawat P; From the Departments of Structural Biology and.; the Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900., Zwieb C; the Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900., Kodali RB; From the Departments of Structural Biology and., Hinck CS; From the Departments of Structural Biology and.; the Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900., Hanna RD; Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 and., Krzysiak TC; From the Departments of Structural Biology and., Ilangovan U; the Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900., Cano KE; the Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900., Hinck G; From the Departments of Structural Biology and.; the Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900., Vonberg M; the Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900., McCabe M; the Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900., Hinck AP; From the Departments of Structural Biology and ahinck@pitt.edu.; the Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2019 Mar 01; Vol. 294 (9), pp. 3065-3080. Date of Electronic Publication: 2018 Dec 31.
DOI: 10.1074/jbc.RA118.005210
Abstrakt: 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.
(© 2019 Henen et al.)
Databáze: MEDLINE
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