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

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 Unione, María Jesús Moure, Mikel Azkargorta, Unai Atxabal, Klaudia Sobczak, Felix Elortza, James D. Sutherland, Rosa Barrio, Filipa Marcelo, Jesús Jiménez-Barbero (), Asis Palazon () and June Ereño-Orbea ()
Additional contact information
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
Helena Coelho: Associate Laboratory i4HB—Institute for Health and Bioeconomy, 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
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
Jesús Jiménez-Barbero: Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park
Asis Palazon: Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park
June Ereño-Orbea: Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39119-8

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