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Structural basis of Fusobacterium nucleatum adhesin Fap2 interaction with receptors on cancer and immune cells

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  • Felix Schöpf

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
    Freie Universität Berlin)

  • Gian L. Marongiu

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
    Freie Universität Berlin)

  • Klaudia Milaj

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
    University of Potsdam)

  • Thiemo Sprink

    (Core Facility for Cryo Electron Microscopy of the Charité—Universitätsmedizin Berlin at the Max Delbrück Center
    Max Delbrück Center for Molecular Medicine, Technology Platform Cryo-EM)

  • Judith Kikhney

    (University of Leipzig Medical Center)

  • Annette Moter

    (University of Leipzig Medical Center)

  • Daniel Roderer

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP))

Abstract

Fusobacterium nucleatum is overrepresented in the colon microbiome of colorectal cancer patients and has been associated with tumor growth enhancement and metastasis. A pivotal pathogenic factor, the autotransporter adhesin Fap2, facilitates association to cancer and immune cells via the receptors Gal-GalNAc and TIGIT, respectively, leading to deactivation of immune cells. Mechanistic details of the Fap2/TIGIT interaction remain elusive as no structural data are available. Here, we report a system to recombinantly express functional Fap2 on the Escherichia coli surface, which interacts with Gal-GalNAc on cancer cells and with purified TIGIT with submicromolar affinity. Cryo-EM structures of Fap2, alone and in complex with TIGIT, show that the elongated ~50 nm long Fap2 extracellular region binds to TIGIT on its membrane-distal tip via an extension of a β-helix domain. Moreover, by combining structure predictions, cryo-EM, docking and molecular dynamics simulations, we identified a binding pit for Gal-GalNAc on the tip of Fap2.

Suggested Citation

  • Felix Schöpf & Gian L. Marongiu & Klaudia Milaj & Thiemo Sprink & Judith Kikhney & Annette Moter & Daniel Roderer, 2025. "Structural basis of Fusobacterium nucleatum adhesin Fap2 interaction with receptors on cancer and immune cells," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63451-w
    DOI: 10.1038/s41467-025-63451-w
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