Solution NMR Analyses of the C-type Carbohydrate Recognition Domain of DC-SIGNR Protein Reveal Different Binding Modes for HIV-derived Oligosaccharides and Smaller Glycan Fragments

Probert, Fay; Whittaker, Sara B.-M.; Crispin, Max; Mitchell, Daniel A.; Dixon, Ann M.

doi:10.1074/jbc.m113.458299

Cited by 20 publications

(31 citation statements)

References 64 publications

(82 reference statements)

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“…This behavior can be of the utmost importance in the signaling transmission of MGL to the immune cells. In fact, the signaling transmission of C‐type immune lectins is usually accompanied by conformational changes on the CRD structure induced by the ligand binding . On this basis, it is tempting to speculate that by modulating the structure/dynamics of MGL‐CRD with distinct ligands it is possible to modify the signaling outcome in immune cells.…”

Section: Resultsmentioning

confidence: 99%

The Plasticity of the Carbohydrate Recognition Domain Dictates the Exquisite Mechanism of Binding of Human Macrophage Galactose‐Type Lectin

Diniz

Coelho

Dias

et al. 2019

Chemistry A European J

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The human macrophage galactose‐type lectin (MGL), expressed on macrophages and dendritic cells (DCs), modulates distinct immune cell responses by recognizing N‐acetylgalactosamine (GalNAc) containing structures present on pathogens, self‐glycoproteins, and tumor cells. Herein, NMR spectroscopy and molecular dynamics (MD) simulations were used to investigate the structural preferences of MGL against different GalNAc‐containing structures derived from the blood group A antigen, the Forssman antigen, and the GM2 glycolipid. NMR spectroscopic analysis of the MGL carbohydrate recognition domain (MGL‐CRD, C181‐H316) in the absence and presence of methyl α‐GalNAc (α‐MeGalNAc), a simple monosaccharide, shows that the MGL‐CRD is highly dynamic and its structure is strongly altered upon ligand binding. This plasticity of the MGL‐CRD structure explains the ability of MGL to accommodate different GalNAc‐containing molecules. However, key differences are observed in the recognition process depending on whether the GalNAc is part of the blood group A antigen, the Forssman antigen, or GM2‐derived structures. These results are in accordance with molecular dynamics simulations that suggest the existence of a distinct MGL binding mechanism depending on the context of GalNAc moiety presentation. These results afford new perspectives for the rational design of GalNAc modifications that fine tune MGL immune responses in distinct biological contexts, especially in malignancy.

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Section: Resultsmentioning

confidence: 99%

The Plasticity of the Carbohydrate Recognition Domain Dictates the Exquisite Mechanism of Binding of Human Macrophage Galactose‐Type Lectin

Diniz

Coelho

Dias

et al. 2019

Chemistry A European J

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“…In fact, such weak interactions are by no means extra-ordinary in protein-carbohydrate interactions(39). Specifically, the well studied interactions between influenza A viral hemagglutinin monomer and its sialyated N-glycan receptor possess dissociation constants in the millimolar range,(40) as does the interaction between high mannose N-glycan and the immune receptor DC-SIGN (41). These weak interactions are still relevant because most protein-carbohydrate interactions rely on multivalency and avidity effects to achieve sufficient binding affinity.…”

Section: Discussionmentioning

confidence: 99%

The Novel Heparin-Binding Motif in Decorin-Binding Protein A from Strain B31 of Borrelia burgdorferi Explains the Higher Binding Affinity

Morgan

Wang

2013

Biochemistry

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Decorin-binding protein A (DBPA), a glycosaminoglycan (GAG) binding lipoprotein found in Borrelia burgdorferi, is crucial to the transmission of Lyme disease in its earliest stages. Due to its role in the initial transmission of the disease, DBPA is an ideal target for vaccine development. DBPA sequences from different strains also contain considerable heterogeneity, leading to differing affinities for GAGs and proteoglycans among different DBPA sequences. Through biophysical and structural analysis of DBPA from the strain B31, we have discovered a novel and important GAG-binding epitope in B31 DBPA. Removal of the epitope greatly attenuated its affinity for DBPA and may explain the differential GAG affinities seen in DBPAs from other strains of Borrelia burgdorferi. Paramagnetic perturbation of the protein with TEMPO-labeled heparin fragments showed bound GAGs are located close to the linker region containing the BXBB motif plays a significant role in determining affinity and orientation of GAG-binding to DBPA is specific. Thermodynamic contributions of the new motif to GAG binding was also characterized with both NMR and ITC and compared with other DBPA residues previously known to be involved in GAG interactions. These analyses showed the motif is as important as other known binding epitopes. The discovery of the motif offers a possible structural explanation to the previous observed differences in GAG affinities of DBPA variants from different Borrelia strains and increases our understanding of DBPA-GAG interactions.

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“…Typical CLRs that simply recognize sugars, such as DC-SIGNR and CEL-IV, exhibit remarkably low affinities (K d ∼mM) (32,33). They require multiple valencies of sugar ligands to mediate signaling.…”

Section: Discussionmentioning

confidence: 99%

Structural analysis for glycolipid recognition by the C-type lectins Mincle and MCL

Furukawa

Kamishikiryo

Mori

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

155

206

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Mincle [macrophage inducible Ca2+ -dependent (C-type) lectin; CLEC4E] and MCL (macrophage C-type lectin; CLEC4D) are receptors for the cord factor TDM (trehalose-6,6′-dimycolate), a unique glycolipid of mycobacterial cell-surface components, and activate immune cells to confer adjuvant activity. Although it is known that receptor-TDM interactions require both sugar and lipid moieties of TDM, the mechanisms of glycolipid recognition by Mincle and MCL remain unclear. We here report the crystal structures of Mincle, MCL, and the Mincle-citric acid complex. The structures revealed that these receptors are capable of interacting with sugar in a Ca 2+ -dependent manner, as observed in other C-type lectins. However, Mincle and MCL uniquely possess shallow hydrophobic regions found adjacent to their putative sugar binding sites, which reasonably locate for recognition of fatty acid moieties of glycolipids. Functional studies using mutant receptors as well as glycolipid ligands support this deduced binding mode. These results give insight into the molecular mechanism of glycolipid recognition through C-type lectin receptors, which may provide clues to rational design for effective adjuvants.X-ray crystallography | innate immunity | mycobacteria | pattern-recognition receptors | myeloid cells

show abstract

Solution NMR Analyses of the C-type Carbohydrate Recognition Domain of DC-SIGNR Protein Reveal Different Binding Modes for HIV-derived Oligosaccharides and Smaller Glycan Fragments

Cited by 20 publications

References 64 publications

The Plasticity of the Carbohydrate Recognition Domain Dictates the Exquisite Mechanism of Binding of Human Macrophage Galactose‐Type Lectin

The Plasticity of the Carbohydrate Recognition Domain Dictates the Exquisite Mechanism of Binding of Human Macrophage Galactose‐Type Lectin

The Novel Heparin-Binding Motif in Decorin-Binding Protein A from Strain B31 of Borrelia burgdorferi Explains the Higher Binding Affinity

Structural analysis for glycolipid recognition by the C-type lectins Mincle and MCL

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