Conformations, dynamics and interactions of di-, tri- and pentamannoside with mannose binding lectin: a molecular dynamics study

Mazumder, Parichita; Mukhopadhyay, Chaitali

doi:10.1016/j.carres.2011.11.021

Cited by 4 publications

(2 citation statements)

References 57 publications

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“…In conclusion, our data show that HNE interacts with human MBL in vitro and that the N-glycosylation of HNE facilitates binding through paucimannosidic ligand/receptor mechanisms like previously reported interactions of highly mannosylated glycoproteins to MBL (99,100). It is tempting to speculate that neutrophils synthesize a spectrum of related glycoforms of HNE spanning high-affinity (containing up to three paucimannosidic moieties, two being M2F) to low-affinity (up to two sialoglycans) variants to fine-tune the amount of binding to MBL and possibly to other mrCLRs e.g.…”

Section: Fig 2 Uniform But Site-specific N-glycosylation Of Hne Ressupporting

confidence: 86%

Paucimannose-Rich N-glycosylation of Spatiotemporally Regulated Human Neutrophil Elastase Modulates Its Immune Functions*.

Loke

Østergaard

Heegaard

et al. 2017

Molecular & Cellular Proteomics

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Human neutrophil elastase (HNE) is an important -glycosylated serine protease in the innate immune system, but the structure and immune-modulating functions of HNE-glycosylation remain undescribed. Herein, LC-MS/MS-based glycan, glycopeptide and glycoprotein profiling were utilized to first determine the heterogeneous -glycosylation of HNE purified from neutrophil lysates and then from isolated neutrophil granules of healthy individuals. The spatiotemporal expression of HNE during neutrophil activation and the biological importance of its-glycosylation were also investigated using immunoblotting, cell surface capture, native MS, receptor interaction, protease inhibition, and bacteria growth assays. Site-specific HNE glycoprofiling demonstrated that unusual paucimannosidic -glycans, particularly Manα1,6Manβ1,4GlcNAcβ1,4(Fucα1,6)GlcNAcβ, predominantly occupied Asn124 and Asn173. The equally unusual core fucosylated monoantenna complex-type-sialoglycans also decorated these two fully occupied sites. In contrast, the mostly unoccupied Asn88 carried nonfucosylated paucimannosidic -glycans probably resulting from low glycosylation site solvent accessibility. Asn185 was not glycosylated. Subcellular- and site-specific glycoprofiling showed highly uniform-glycosylation of HNE residing in distinct neutrophil compartments. Stimulation-induced cell surface mobilization demonstrated a spatiotemporal regulation, but not cell surface-specific glycosylation signatures, of HNE in activated human neutrophils. The three glycosylation sites of HNE were located distal to the active site indicating glycan functions other than interference with HNE enzyme activity. Functionally, the paucimannosidic HNE glycoforms displayed preferential binding to human mannose binding lectin compared with the HNE sialoglycoforms, suggesting a glycoform-dependent involvement of HNE in complement activation. The heavily -glycosylated HNE protease inhibitor, α1-antitrypsin, displayed concentration-dependent complex formation and preferred glycoform-glycoform interactions with HNE. Finally, both enzymatically active HNE and isolated HNE-glycans demonstrated low micromolar concentration-dependent growth inhibition of clinically-relevant , suggesting some bacteriostatic activity is conferred by the HNE-glycans. Taken together, these observations support that the unusual HNE -glycosylation, here reported for the first time, is involved in modulating multiple immune functions central to inflammation and infection.

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Section: Fig 2 Uniform But Site-specific N-glycosylation Of Hne Ressupporting

confidence: 86%

Paucimannose-Rich N-glycosylation of Spatiotemporally Regulated Human Neutrophil Elastase Modulates Its Immune Functions*.

Loke

Østergaard

Heegaard

et al. 2017

Molecular & Cellular Proteomics

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“…Although dozens of crystal structures of HA and of several complexes with antibody Fab fragments have been reported, − no protein–HA complexes with innate host defense proteins have been studied at the atomic level. Previous computational studies of lectins with anti-influenza activity, namely of SP-D, , mannan-binding lectin, and galectins, , have focused on complexes with isolated carbohydrate ligands rather than with viral glycoproteins. Similarly, computational studies of hemagglutinins − have not addressed binding to lectins; a major barrier has been the large size of the system, necessitating advanced computational approaches.…”

mentioning

confidence: 99%

Molecular Mechanisms of Inhibition of Influenza by Surfactant Protein D Revealed by Large-Scale Molecular Dynamics Simulation

et al. 2013

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Surfactant protein D (SP-D), a mammalian C-type lectin, is the primary innate inhibitor of influenza A virus (IAV) in the lung. SP-D interactions with highly branched viral N-linked glycans on hemagglutinin (HA), an abundant IAV envelope protein and critical virulence factor, promote viral aggregation and neutralization through as yet unknown molecular mechanisms. Two truncated human SP-D forms, wild-type (WT) and double mutant D325A+R343V, representing neck and carbohydrate recognition domains are compared in this study. Whereas both WT and D325A+R343V bind to isolated glycosylated HA, WT does not inhibit IAV in neutralization assays; in contrast, D325A+R343V neutralization compares well with full-length native SP-D. To elucidate the mechanism for these biochemical observations, we have solved crystal structures of D325A+R343V in the presence and absence of a viral nonamannoside (Man9). Based on the D325A+R343V/Man9 structure and other crystallographic data, models of complexes between HA and WT or D325A+R343V were produced and subjected to molecular dynamics. Simulations reveal that whereas WT and D325A+R343V both block the sialic acid receptor site of HA, the D325A+R343V complex is more stable, with stronger binding due to additional hydrogen bonds and hydrophobic interactions with HA residues. Furthermore, the blocking mechanism of HA differs for WT and D325A+R343V due to alternate glycan binding modes. The combined results suggest a mechanism through which the mode of SP-D/HA interaction could significantly influence viral aggregation and neutralization. These studies provide the first atomic-level molecular view of an innate host defense lectin inhibiting its viral glycoprotein target.

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Heat capacities and thermodynamic functions of d-ribose and d-mannose

Wang

Zhang

et al. 2018

J Therm Anal Calorim

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Conformations, dynamics and interactions of di-, tri- and pentamannoside with mannose binding lectin: a molecular dynamics study

Cited by 4 publications

References 57 publications

Paucimannose-Rich N-glycosylation of Spatiotemporally Regulated Human Neutrophil Elastase Modulates Its Immune Functions*.

Paucimannose-Rich N-glycosylation of Spatiotemporally Regulated Human Neutrophil Elastase Modulates Its Immune Functions*.

Molecular Mechanisms of Inhibition of Influenza by Surfactant Protein D Revealed by Large-Scale Molecular Dynamics Simulation

Heat capacities and thermodynamic functions of d-ribose and d-mannose

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