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Structural insights into Siglec-15 reveal glycosylation dependency for its interaction with T cells through integrin CD11b

Author

Listed:
  • Maria Pia Lenza

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park)

  • Leire Egia-Mendikute

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park)

  • Asier Antoñana-Vildosola

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park)

  • Cátia O. Soares

    (Associate Laboratory i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology
    UCIBIO, Department of Chemistry, NOVA School of Science and Technology)

  • Helena Coelho

    (Associate Laboratory i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology
    UCIBIO, Department of Chemistry, NOVA School of Science and Technology)

  • Francisco Corzana

    (University of La Rioja, The Center for Research in Chemical Synthesis)

  • Alexandre Bosch

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park)

  • Prodhi Manisha

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park)

  • Jon Imanol Quintana

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park)

  • Iker Oyenarte

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park)

  • Luca Unione

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park
    Ikerbasque, Basque Foundation for Science)

  • María Jesús Moure

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park)

  • Mikel Azkargorta

    (Bizkaia Technology Park)

  • Unai Atxabal

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park)

  • Klaudia Sobczak

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park)

  • Felix Elortza

    (Bizkaia Technology Park)

  • James D. Sutherland

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park)

  • Rosa Barrio

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park)

  • Filipa Marcelo

    (Associate Laboratory i4HB—Institute for Health and Bioeconomy, NOVA School of Science and Technology
    UCIBIO, Department of Chemistry, NOVA School of Science and Technology)

  • Jesús Jiménez-Barbero

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park
    Ikerbasque, Basque Foundation for Science
    University of the Basque Country, EHU-UPV
    Centro de Investigacion Biomedica En Red de Enfermedades Respiratorias)

  • Asis Palazon

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park
    Ikerbasque, Basque Foundation for Science)

  • June Ereño-Orbea

    (Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park
    Ikerbasque, Basque Foundation for Science)

Abstract

Sialic acid-binding Ig-like lectin 15 (Siglec-15) is an immune modulator and emerging cancer immunotherapy target. However, limited understanding of its structure and mechanism of action restrains the development of drug candidates that unleash its full therapeutic potential. In this study, we elucidate the crystal structure of Siglec-15 and its binding epitope via co-crystallization with an anti-Siglec-15 blocking antibody. Using saturation transfer-difference nuclear magnetic resonance (STD-NMR) spectroscopy and molecular dynamics simulations, we reveal Siglec-15 binding mode to α(2,3)- and α(2,6)-linked sialic acids and the cancer-associated sialyl-Tn (STn) glycoform. We demonstrate that binding of Siglec-15 to T cells, which lack STn expression, depends on the presence of α(2,3)- and α(2,6)-linked sialoglycans. Furthermore, we identify the leukocyte integrin CD11b as a Siglec-15 binding partner on human T cells. Collectively, our findings provide an integrated understanding of the structural features of Siglec-15 and emphasize glycosylation as a crucial factor in controlling T cell responses.

Suggested Citation

  • Maria Pia Lenza & Leire Egia-Mendikute & Asier Antoñana-Vildosola & Cátia O. Soares & Helena Coelho & Francisco Corzana & Alexandre Bosch & Prodhi Manisha & Jon Imanol Quintana & Iker Oyenarte & Luca , 2023. "Structural insights into Siglec-15 reveal glycosylation dependency for its interaction with T cells through integrin CD11b," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39119-8
    DOI: 10.1038/s41467-023-39119-8
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    References listed on IDEAS

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    2. Ira Mellman & George Coukos & Glenn Dranoff, 2011. "Cancer immunotherapy comes of age," Nature, Nature, vol. 480(7378), pages 480-489, December.
    3. Paul C. Tumeh & Christina L. Harview & Jennifer H. Yearley & I. Peter Shintaku & Emma J. M. Taylor & Lidia Robert & Bartosz Chmielowski & Marko Spasic & Gina Henry & Voicu Ciobanu & Alisha N. West & M, 2014. "PD-1 blockade induces responses by inhibiting adaptive immune resistance," Nature, Nature, vol. 515(7528), pages 568-571, November.
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