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

Autor: Lenza MP; Chemical Glycobiology lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160, Derio, Bizkaia, Spain., Egia-Mendikute L; Cancer Immunology and Immunotherapy Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Bizkaia, Spain., Antoñana-Vildosola A; Cancer Immunology and Immunotherapy Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Bizkaia, Spain., Soares CO; Associate Laboratory i4HB-Institute for Health and Bioeconomy, NOVA School of Science and Technology, Caparica campus, 2829-516, Caparica, Portugal.; UCIBIO, Department of Chemistry, NOVA School of Science and Technology, Caparica campus, 2829-516, Caparica, Portugal., Coelho H; Associate Laboratory i4HB-Institute for Health and Bioeconomy, NOVA School of Science and Technology, Caparica campus, 2829-516, Caparica, Portugal.; UCIBIO, Department of Chemistry, NOVA School of Science and Technology, Caparica campus, 2829-516, Caparica, Portugal., Corzana F; Department of Chemistry, University of La Rioja, The Center for Research in Chemical Synthesis, Madre de Dios 53, E-26006, Logroño, Spain., Bosch A; Cancer Immunology and Immunotherapy Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Bizkaia, Spain., Manisha P; Cancer Immunology and Immunotherapy Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Bizkaia, Spain., Quintana JI; Chemical Glycobiology lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160, Derio, Bizkaia, Spain., Oyenarte I; Chemical Glycobiology lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160, Derio, Bizkaia, Spain., Unione L; Chemical Glycobiology lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160, Derio, Bizkaia, Spain.; Ikerbasque, Basque Foundation for Science, Bilbao, Spain., Moure MJ; Chemical Glycobiology lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160, Derio, Bizkaia, Spain., Azkargorta M; Proteomics Platform, CIC bioGUNE, CIBERehd, Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160, Derio, Spain., Atxabal U; Chemical Glycobiology lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160, Derio, Bizkaia, Spain., Sobczak K; Chemical Glycobiology lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160, Derio, Bizkaia, Spain., Elortza F; Proteomics Platform, CIC bioGUNE, CIBERehd, Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160, Derio, Spain., Sutherland JD; Ubiquitin-likes and Development Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Bizkaia, Spain., Barrio R; Ubiquitin-likes and Development Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Bizkaia, Spain., Marcelo F; Associate Laboratory i4HB-Institute for Health and Bioeconomy, NOVA School of Science and Technology, Caparica campus, 2829-516, Caparica, Portugal.; UCIBIO, Department of Chemistry, NOVA School of Science and Technology, Caparica campus, 2829-516, Caparica, Portugal., Jiménez-Barbero J; Chemical Glycobiology lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160, Derio, Bizkaia, Spain. jjbarbero@cicbiogune.es.; Ikerbasque, Basque Foundation for Science, Bilbao, Spain. jjbarbero@cicbiogune.es.; Department of Organic & Inorganic Chemistry, Faculty of Science and Technology, University of the Basque Country, EHU-UPV, 48940, Leioa, Bizkaia, Spain. jjbarbero@cicbiogune.es.; Centro de Investigacion Biomedica En Red de Enfermedades Respiratorias, 28029, Madrid, Spain. jjbarbero@cicbiogune.es., Palazon A; Cancer Immunology and Immunotherapy Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Bizkaia, Spain. apalazon@cicbiogune.es.; Ikerbasque, Basque Foundation for Science, Bilbao, Spain. apalazon@cicbiogune.es., Ereño-Orbea J; Chemical Glycobiology lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 800, 48160, Derio, Bizkaia, Spain. jereno@cicbiogune.es.; Ikerbasque, Basque Foundation for Science, Bilbao, Spain. jereno@cicbiogune.es.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Jun 13; Vol. 14 (1), pp. 3496. Date of Electronic Publication: 2023 Jun 13.
DOI: 10.1038/s41467-023-39119-8
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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