Recognition of Complex Core‐Fucosylated N‐Glycans by a Mini Lectin

Cabanettes, Aurore; Perkams, Lukas; Spies, Claudia; Unverzagt, Carlo; Varrot, A.

doi:10.1002/anie.201805165

Cited by 17 publications

(3 citation statements)

References 24 publications

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“…Pholiota squarrosa lectin PhoSL, isolated from a mushroom, specifically recognizes core‐fucosylated N ‐glycans. [ 29 ] Notably, PhoSL is only composed of 40 amino acids, which makes the recombinant expression and genetic manipulation of PhoSL very convenient. [ 30 ] We then used PhoSL as a model system to investigate and manipulate the CH–π interaction involved in recognizing core fucosylated N‐glycans.…”

Section: Resultsmentioning

confidence: 99%

A Computational and Chemical Design Strategy for Manipulating Glycan‐Protein Recognition

Zhu,

Geng,

et al. 2024

Advanced Science

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Glycans are complex biomolecules that encode rich information and regulate various biological processes, such as fertilization, host‐pathogen binding, and immune recognition, through interactions with glycan‐binding proteins. A key driving force for glycan‐protein recognition is the interaction between the π electron density of aromatic amino acid side chains and polarized C─H groups of the pyranose (termed the CH–π interaction). However, the relatively weak binding affinity between glycans and proteins has hindered the application of glycan detection and imaging. Here, computational modeling and molecular dynamics simulations are employed to design a chemical strategy that enhances the CH–π interaction between glycans and proteins by genetically incorporating electron‐rich tryptophan derivatives into a lectin PhoSL, which specifically recognizes core fucosylated N‐linked glycans. This significantly enhances the binding affinity of PhoSL with the core fucose ligand and enables sensitive detection and imaging of core fucosylated glycans in vitro and in xenograft tumors in mice. Further, the study showed that this strategy is applicable to improve the binding affinity of GafD lectin for N‐acetylglucosamine‐containing glycans. The approach thus provides a general and effective way to manipulate glycan‐protein recognition for glycoscience applications.

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Section: Resultsmentioning

confidence: 99%

A Computational and Chemical Design Strategy for Manipulating Glycan‐Protein Recognition

Zhu,

Geng,

et al. 2024

Advanced Science

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“…The importance of a1-6 core-fucose in the recognition was further investigated by a displacement binding assay in the presence of immobilized-hPSA blocked with 1 mg mL À1 PhoSL for 1 h in PBS-Na buffer. Given that the PhoSL lectin specically recognizes core-fucosylated N-glycans, 33 we deemed that the binding of the lectin to hPSA could inhibit the interaction of an aptamer able to recognize this sugar. We nd nearly the same signals as those obtained for unblocked PSA when the assay is performed with PSA-1 (ESI, Fig.…”

Section: Empirical Study Of the Binding Sitementioning

confidence: 99%

Aptamers targeting protein-specific glycosylation in tumor biomarkers: general selection, characterization and structural modeling

et al. 2020

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“…Its trimeric structure was determined by both our group and other researchers, and in this structure, a trisaccharide in the formula fucose(α1–6)[GlcNAc(β1–4)]GlcNAc is recognised in the binding pocket (Fig. 1B ) [ 22 , 23 , 24 ]. In the S protein, more than half of the N‐glycans are core‐fucosylated [ 6 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Core fucose‐specific Pholiota squarrosa lectin (PhoSL) as a potent broad‐spectrum inhibitor of SARS‐CoV‐2 infection

et al. 2022

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike protein (S protein) is highly N‐glycosylated, and a “glycan shield” is formed to limit the access of other molecules; however, a small open area coincides with the interface to the host's receptor and also neutralising antibodies. Most of the variants of concern have mutations in this area, which could reduce the efficacy of existing antibodies. In contrast, N‐glycosylation sites are relatively invariant, and some are essential for infection. Here, we observed that the S proteins of the ancestral (Wuhan) and Omicron strains bind with Pholiota squarrosa lectin (PhoSL), a 40‐amino‐acid chemically synthesised peptide specific to core‐fucosylated N‐glycans. The affinities were at a low nanomolar level, which were ~ 1000‐fold stronger than those between PhoSL and the core‐fucosylated N‐glycans at the micromolar level. We demonstrated that PhoSL inhibited infection by both strains at similar submicromolar levels, suggesting its broad‐spectrum effect on SARS‐CoV‐2 variants. Cryogenic electron microscopy revealed that PhoSL caused an aggregation of the S protein, which was likely due to the multivalence of both the trimeric PhoSL and S protein. This characteristic is likely relevant to the inhibitory mechanism. Structural modelling of the PhoSL–S protein complex indicated that PhoSL was in contact with the amino acids of the S protein, which explains the enhanced affinity with S protein and also indicates the significant potential for developing specific binders by the engineering of PhoSL.

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Recognition of Complex Core‐Fucosylated N‐Glycans by a Mini Lectin

Cited by 17 publications

References 24 publications

A Computational and Chemical Design Strategy for Manipulating Glycan‐Protein Recognition

A Computational and Chemical Design Strategy for Manipulating Glycan‐Protein Recognition

Aptamers targeting protein-specific glycosylation in tumor biomarkers: general selection, characterization and structural modeling

Core fucose‐specific Pholiota squarrosa lectin (PhoSL) as a potent broad‐spectrum inhibitor of SARS‐CoV‐2 infection

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