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PreprintCited by 2Developmental Biology and Gene RegulationWnt/β-catenin signaling in development and cancerTGF-β signaling in diseases

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An avidity-driven mechanism of extracellular BMP regulation by Twisted gastrulation

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Moore, Gareth, Revici, Raluca, Forbes Beadle, Lauren, Sutcliffe, Catherine, Birchenough, Holly, Baldock, Clair, Ashe, Hilary L·2024·Development
DOI 10.1101/2024.07.08.602551

Preprint — published as 10.1242/dev.204584 · Paper page

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Abstract

During dorsoventral patterning of bilaterian embryos, the conserved regulator Twisted gastrulation (Tsg) modulates BMP signalling by binding Chordin/Short gastrulation (Sog). Here we elucidate the mechanism by which Tsg interacts with Sog/Chordin to promote formation of the inhibitory Tsg-Sog/Chordin-BMP complex and regulate BMP signalling extracellularly. We identify and validate in vitro a hydrophobic interface in the Tsg C-terminal domain that binds Chordin. Mutation of this epitope in Drosophila Tsg (Tsg L100A ) results in an unexpectedly mild perturbation to embryonic BMP gradient formation. We show that a protosome-specific Tsg C-terminal extension also binds Sog, and the presence of this second binding site allows partial rescue of Sog interaction with Tsg L100A in the presence of BMP. Consistent with this, a truncated Tsg protein lacking both Sog binding regions is unable to support BMP gradient formation in vivo . As our data show that disruption of either Sog binding site in Tsg, but not both, can be overcome by Tsg-BMP and Sog-BMP interactions, we present a new avidity-driven mechanism of BMP gradient formation that will be relevant to a broad range of developmental contexts. Summary statement: Identification and mutational analysis of the binding epitopes that mediate Twisted gastrulation interaction with Short gastrulation/Chordin reveals an avidity-based model of embryonic BMP gradient formation.

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Metadata

Authors
Moore, G., Revici, R., Forbes Beadle, L., Sutcliffe, C., Birchenough, H., Baldock, C., & Ashe, H. L.
Affiliations
  • University of Manchester (GB)
  • Manchester Academic Health Science Centre (GB)
Corresponding author
  • Baldock, Clair
  • Ashe, Hilary L
ORCID
Venue
Development
Publisher
openRxiv
Published
2024-07-10
Volume
153
Issue
16
ISSN
0950-1991 (ISSN-L)
DOI
10.1101/2024.07.08.602551
OpenAlex
W7119117211
Cited by
2
References
1
Citations by year
2026: 2
FWCI
4.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Development (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
Funders
Biotechnology and Biological Sciences Research Council (BB/V008099/1, BB/M011208/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
twisted gastrulation, chordin, short gastrulation, BMP signaling, avidity, protein-protein interaction, hydrophobic interface, C-terminal domain, dorsoventral patterning, Drosophila embryo
MeSH terms
Animals, Binding Sites, Drosophila melanogaster, Embryo, Nonmammalian, Glycoproteins, Mutation, Protein Binding, Signal Transduction, Gene Expression Regulation, Developmental, Bone Morphogenetic Proteins, Body Patterning, Drosophila Proteins, Intercellular Signaling Peptides and Proteins, Gastrulation

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