Molecular mechanism of BMP signal control by Twisted gastrulation

Tomas Malinauskas (), Gareth Moore, Amalie F. Rudolf, Holly Eggington, Hayley L. Belnoue-Davis, Kamel El Omari, Samuel C. Griffiths, Rachel E. Woolley, Ramona Duman, Armin Wagner, Simon J. Leedham, Clair Baldock, Hilary L. Ashe () and Christian Siebold ()
Additional contact information
Tomas Malinauskas: University of Oxford
Gareth Moore: University of Manchester
Amalie F. Rudolf: University of Oxford
Holly Eggington: University of Oxford
Hayley L. Belnoue-Davis: University of Oxford
Kamel El Omari: Harwell Science and Innovation Campus
Samuel C. Griffiths: University of Oxford
Rachel E. Woolley: University of Oxford
Ramona Duman: Harwell Science and Innovation Campus
Armin Wagner: Harwell Science and Innovation Campus
Simon J. Leedham: University of Oxford
Clair Baldock: University of Manchester
Hilary L. Ashe: University of Manchester
Christian Siebold: University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Twisted gastrulation (TWSG1) is an evolutionarily conserved secreted glycoprotein which controls signaling by Bone Morphogenetic Proteins (BMPs). TWSG1 binds BMPs and their antagonist Chordin to control BMP signaling during embryonic development, kidney regeneration and cancer. We report crystal structures of TWSG1 alone and in complex with a BMP ligand, Growth Differentiation Factor 5. TWSG1 is composed of two distinct, disulfide-rich domains. The TWSG1 N-terminal domain occupies the BMP type 1 receptor binding site on BMPs, whereas the C-terminal domain binds to a Chordin family member. We show that TWSG1 inhibits BMP function in cellular signaling assays and mouse colon organoids. This inhibitory function is abolished in a TWSG1 mutant that cannot bind BMPs. The same mutation in the Drosophila TWSG1 ortholog Tsg fails to mediate BMP gradient formation required for dorsal-ventral axis patterning of the early embryo. Our studies reveal the evolutionarily conserved mechanism of BMP signaling inhibition by TWSG1.

Date: 2024
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DOI: 10.1038/s41467-024-49065-8

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