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Molecular mechanism of BMP signal control by Twisted gastrulation.
- Source :
-
Nature communications [Nat Commun] 2024 Jun 11; Vol. 15 (1), pp. 4976. Date of Electronic Publication: 2024 Jun 11. - Publication Year :
- 2024
-
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.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Mice
Humans
Drosophila Proteins metabolism
Drosophila Proteins genetics
Drosophila Proteins chemistry
Glycoproteins metabolism
Glycoproteins genetics
Intercellular Signaling Peptides and Proteins metabolism
Intercellular Signaling Peptides and Proteins genetics
Binding Sites
Protein Domains
Protein Binding
Organoids metabolism
Organoids embryology
HEK293 Cells
Gastrulation genetics
Mutation
Crystallography, X-Ray
Drosophila melanogaster embryology
Drosophila melanogaster metabolism
Drosophila melanogaster genetics
Proteins
Bone Morphogenetic Proteins metabolism
Bone Morphogenetic Proteins genetics
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 38862520
- Full Text :
- https://doi.org/10.1038/s41467-024-49065-8