期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：29
页码：E4170-E4179
DOI：10.1073/pnas.1602214113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Siglec-8 is a human immune-inhibitory receptor that, when engaged by specific self-glycans, triggers eosinophil apoptosis and inhibits mast cell degranulation, providing an endogenous mechanism to down-regulate immune responses of these central inflammatory effector cells. Here we used solution NMR spectroscopy to dissect the fine specificity of Siglec-8 toward different sialylated and sulfated carbohydrate ligands and determined the structure of the Siglec-8 lectin domain in complex with its prime glycan target 6′-sulfo sialyl Lewisx. A canonical motif for sialic acid recognition, extended by a secondary motif formed by unique loop regions, recognizing 6-O–sulfated galactose dictates tight specificity distinct from other Siglec family members and any other endogenous glycan recognition receptors. Structure-guided mutagenesis revealed key contacts of both interfaces to be equally essential for binding. Our work provides critical structural and mechanistic insights into how Siglec-8 selectively recognizes its glycan target, rationalizes the functional impact of site-specific glycan sulfation in modulating this lectin–glycan interaction, and will enable the rational design of Siglec-8–targeted agonists to treat eosinophil- and mast cell-related allergic and inflammatory diseases, such as asthma.
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