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Molecular mechanism of BMP signal control by Twisted gastrulation

Author

Listed:
  • Tomas Malinauskas

    (University of Oxford)

  • Gareth Moore

    (University of Manchester)

  • Amalie F. Rudolf

    (University of Oxford)

  • Holly Eggington

    (University of Oxford
    Oxford National Institute for Health Research Biomedical Research Centre)

  • Hayley L. Belnoue-Davis

    (University of Oxford
    Oxford National Institute for Health Research Biomedical Research Centre)

  • Kamel El Omari

    (Harwell Science and Innovation Campus)

  • Samuel C. Griffiths

    (University of Oxford
    Milton Park)

  • Rachel E. Woolley

    (University of Oxford
    Atlas Building)

  • Ramona Duman

    (Harwell Science and Innovation Campus)

  • Armin Wagner

    (Harwell Science and Innovation Campus)

  • Simon J. Leedham

    (University of Oxford
    Oxford National Institute for Health Research Biomedical Research Centre)

  • Clair Baldock

    (University of Manchester)

  • Hilary L. Ashe

    (University of Manchester)

  • Christian Siebold

    (University of Oxford)

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.

Suggested Citation

  • 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. Leed, 2024. "Molecular mechanism of BMP signal control by Twisted gastrulation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49065-8
    DOI: 10.1038/s41467-024-49065-8
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    References listed on IDEAS

    as
    1. Hilary L. Ashe & Michael Levine, 1999. "Local inhibition and long-range enhancement of Dpp signal transduction by Sog," Nature, Nature, vol. 398(6726), pages 427-431, April.
    2. Jeffrey J. Ross & Osamu Shimmi & Peter Vilmos & Anna Petryk & Hyon Kim & Karin Gaudenz & Spencer Hermanson & Stephen C. Ekker & Michael B. O'Connor & J. Lawrence Marsh, 2001. "Twisted gastrulation is a conserved extracellular BMP antagonist," Nature, Nature, vol. 410(6827), pages 479-483, March.
    3. Ian C. Scott & Ira L. Blitz & William N. Pappano & Sarah A. Maas & Ken W. Y. Cho & Daniel S. Greenspan, 2001. "Homologues of Twisted gastrulation are extracellular cofactors in antagonism of BMP signalling," Nature, Nature, vol. 410(6827), pages 475-478, March.
    4. Ian C. Scott & Ira L. Blitz & William N. Pappano & Sarah A. Maas & Ken W. Y. Cho & Daniel S. Greenspan, 2001. "Erratum: Homologues of Twisted gastrulation are extracellular cofactors in antagonism of BMP signalling," Nature, Nature, vol. 411(6838), pages 720-720, June.
    5. Yu-Chiun Wang & Edwin L. Ferguson, 2005. "Spatial bistability of Dpp–receptor interactions during Drosophila dorsal–ventral patterning," Nature, Nature, vol. 434(7030), pages 229-234, March.
    6. Jay Groppe & Jason Greenwald & Ezra Wiater & Joaquin Rodriguez-Leon & Aris N. Economides & Witek Kwiatkowski & Markus Affolter & Wylie W. Vale & Juan Carlos Izpisua Belmonte & Senyon Choe, 2002. "Structural basis of BMP signalling inhibition by the cystine knot protein Noggin," Nature, Nature, vol. 420(6916), pages 636-642, December.
    7. Michael Oelgeschläger & Juan Larraín & Douglas Geissert & Eddy M. De Robertis, 2000. "The evolutionarily conserved BMP-binding protein Twisted gastrulation promotes BMP signalling," Nature, Nature, vol. 405(6788), pages 757-763, June.
    8. Chenbei Chang & Douglas A. Holtzman & Samantha Chau & Troy Chickering & Elizabeth A. Woolf & Lisa M. Holmgren & Jana Bodorova & David P. Gearing & William E. Holmes & Ali H. Brivanlou, 2001. "Twisted gastrulation can function as a BMP antagonist," Nature, Nature, vol. 410(6827), pages 483-487, March.
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