2N7B

Solution structure of the human Siglec-8 lectin domain in complex with 6'sulfo sialyl Lewisx

Summary for 2N7B

• Entry DOI: 10.2210/pdb2n7b/pdb
• Related: 2N7A
• NMR Information: BMRB: 25799
• Descriptor: Sialic acid-binding Ig-like lectin 8, N-acetyl-alpha-neuraminic acid-(2-3)-6-O-sulfo-beta-D-galactopyranose-(1-4)-[alpha-L-fucopyranose-(1-3)]2-acetamido-2-deoxy-beta-D-glucopyranose, 3-aminopropan-1-ol (3 entities in total)
• Functional Keywords: sialic acid-binding immunoglobulin-like lectin 8, siglec8, saf-2, i-type lectin, carbohydrate-binding receptor, carbohydrate recognition, protein-glycan complex, sulfated sialyl lewis x, structural protein
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: Q9NYZ4
• Total number of polymer chains: 1
• Total formula weight: 17641.38

Authors

Proepster, J.M.,Yang, F.,Rabbani, S.,Ernst, B.,Allain, F.H.-T.,Schubert, M. (deposition date: 2015-09-07, release date: 2016-07-06, Last modification date: 2024-11-20)

Primary citation

Propster, J.M.,Yang, F.,Rabbani, S.,Ernst, B.,Allain, F.H.,Schubert, M.
Structural basis for sulfation-dependent self-glycan recognition by the human immune-inhibitory receptor Siglec-8.
Proc.Natl.Acad.Sci.USA, 113:E4170-E4179, 2016

PubMed 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.

PubMed: 27357658
DOI: 10.1073/pnas.1602214113

Experimental method

SOLUTION NMR