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Molecular mechanism of BMP signal control by Twisted gastrulation.

Authors :
Malinauskas T
Moore G
Rudolf AF
Eggington H
Belnoue-Davis HL
El Omari K
Griffiths SC
Woolley RE
Duman R
Wagner A
Leedham SJ
Baldock C
Ashe HL
Siebold C
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).)

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