Structures of TGF-β with betaglycan and signaling receptors reveal mechanisms of complex assembly and signaling

Łukasz Wieteska, Alexander B. Taylor, Emma Punch, Jonathan A. Coleman, Isabella O. Conway, Yeu-Farn Lin, Chang-Hyeock Byeon, Cynthia S. Hinck, Troy Krzysiak, Rieko Ishima, Fernando López-Casillas, Peter Cherepanov, Daniel J. Bernard, Caroline S. Hill () and Andrew P. Hinck ()
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Łukasz Wieteska: University of Pittsburgh
Alexander B. Taylor: The University of Texas Health Science Center at San Antonio
Emma Punch: The Francis Crick Institute
Jonathan A. Coleman: University of Pittsburgh
Isabella O. Conway: University of Pittsburgh
Yeu-Farn Lin: McGill University
Chang-Hyeock Byeon: University of Pittsburgh
Cynthia S. Hinck: University of Pittsburgh
Troy Krzysiak: University of Pittsburgh
Rieko Ishima: University of Pittsburgh
Fernando López-Casillas: UNAM
Peter Cherepanov: The Francis Crick Institute
Daniel J. Bernard: McGill University
Caroline S. Hill: The Francis Crick Institute
Andrew P. Hinck: University of Pittsburgh

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Betaglycan (BG) is a transmembrane co-receptor of the transforming growth factor-β (TGF-β) family of signaling ligands. It is essential for embryonic development, tissue homeostasis and fertility in adults. It functions by enabling binding of the three TGF-β isoforms to their signaling receptors and is additionally required for inhibin A (InhA) activity. Despite its requirement for the functions of TGF-βs and InhA in vivo, structural information explaining BG ligand selectivity and its mechanism of action is lacking. Here, we determine the structure of TGF-β bound both to BG and the signaling receptors, TGFBR1 and TGFBR2. We identify key regions responsible for ligand engagement, which has revealed binding interfaces that differ from those described for the closely related co-receptor of the TGF-β family, endoglin, thus demonstrating remarkable evolutionary adaptation to enable ligand selectivity. Finally, we provide a structural explanation for the hand-off mechanism underlying TGF-β signal potentiation.

Date: 2025
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DOI: 10.1038/s41467-025-56796-9

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