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Structural basis for sulfation-dependent self-glycan recognition by the human immune-inhibitory receptor Siglec-8

Pröpster, Johannes M. and Yang, Fan and Rabbani, Said and Ernst, Beat and Allain, Frédéric H.-T. and Schubert, Mario. (2016) Structural basis for sulfation-dependent self-glycan recognition by the human immune-inhibitory receptor Siglec-8. Proceedings of the National Academy of Sciences of the United States of America, 113 (29). pp. 4170-4179.

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Official URL: http://edoc.unibas.ch/52926/

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Abstract

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 Lewis(x) 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.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Yang, Fan and Rabbani, Said and Ernst, Beat
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:National Academy of Sciences
ISSN:0027-8424
e-ISSN:1091-6490
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:28 Nov 2017 11:16
Deposited On:25 Oct 2017 14:40

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