| Structural highlights
Publication Abstract from PubMed
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 alpha(2,3)- and alpha(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 alpha(2,3)- and alpha(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.
Structural insights into Siglec-15 reveal glycosylation dependency for its interaction with T cells through integrin CD11b.,Lenza MP, Egia-Mendikute L, Antonana-Vildosola A, Soares CO, Coelho H, Corzana F, Bosch A, Manisha P, Quintana JI, Oyenarte I, Unione L, Moure MJ, Azkargorta M, Atxabal U, Sobczak K, Elortza F, Sutherland JD, Barrio R, Marcelo F, Jimenez-Barbero J, Palazon A, Ereno-Orbea J Nat Commun. 2023 Jun 13;14(1):3496. doi: 10.1038/s41467-023-39119-8. PMID:37311743[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lenza MP, Egia-Mendikute L, Antoñana-Vildosola A, Soares CO, Coelho H, Corzana F, Bosch A, Manisha P, Quintana JI, Oyenarte I, Unione L, Moure MJ, Azkargorta M, Atxabal U, Sobczak K, Elortza F, Sutherland JD, Barrio R, Marcelo F, Jiménez-Barbero J, Palazon A, Ereño-Orbea J. Structural insights into Siglec-15 reveal glycosylation dependency for its interaction with T cells through integrin CD11b. Nat Commun. 2023 Jun 13;14(1):3496. PMID:37311743 doi:10.1038/s41467-023-39119-8
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