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

AI Article Synopsis

  • Siglec-15 is a protein that helps regulate the immune system and is a potential target for cancer therapies, but its exact structure and function are not well understood.
  • This study successfully determined the crystal structure of Siglec-15 and its interaction with specific sugars (sialic acids) using advanced techniques like co-crystallization and NMR spectroscopy.
  • The researchers found that Siglec-15 binds to T cells through different sugar linkages and identified CD11b, a leukocyte integrin, as a partner in this binding, highlighting the importance of glycosylation in T cell immunity.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10264397PMC
http://dx.doi.org/10.1038/s41467-023-39119-8DOI Listing

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