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15 pages, 2654 KiB

Open AccessArticle

BC2L-C N-Terminal Lectin Domain Complexed with Histo Blood Group Oligosaccharides Provides New Structural Information

by Rafael Bermeo, Anna Bernardi and Annabelle Varrot

Molecules 2020, 25(2), 248; https://doi.org/10.3390/molecules25020248 - 7 Jan 2020

Cited by 7 | Viewed by 4094

Abstract

Lectins mediate adhesion of pathogens to host tissues, filling in a key role in the first steps of infection. Belonging to the opportunistic pathogen Burkholderia cenocepacia, BC2L-C is a superlectin with dual carbohydrate specificity, believed to mediate cross-linking between bacteria and host [...] Read more.

Lectins mediate adhesion of pathogens to host tissues, filling in a key role in the first steps of infection. Belonging to the opportunistic pathogen Burkholderia cenocepacia, BC2L-C is a superlectin with dual carbohydrate specificity, believed to mediate cross-linking between bacteria and host cells. Its C-terminal domain binds to bacterial mannosides while its N-terminal domain (BCL2-CN) recognizes fucosylated human epitopes. BC2L-CN presents a tumor necrosis factor alpha (TNF-α) fold previously unseen in lectins with a novel fucose binding mode. We report, here, the production of a novel recombinant form of BC2L-CN (rBC2L-CN2), which allowed better protein stability and unprecedented co-crystallization with oligosaccharides. Isothermal calorimetry measurements showed no detrimental effect on ligand binding and data were obtained on the binding of Globo H hexasaccharide and l-galactose. Crystal structures of rBC2L-CN2 were solved in complex with two blood group antigens: H-type 1 and H-type 3 (Globo H) by X-ray crystallography. They provide new structural information on the binding site, of importance for the structural-based design of glycodrugs as new antimicrobials with antiadhesive properties. Full article

(This article belongs to the Special Issue Lectins: From Biochemical and Structural Studies to Biotechnological and Biomedical Applications)

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18 pages, 1504 KiB

Open AccessArticle

Glycomic Signatures of Plasma IgG Improve Preoperative Prediction of the Invasiveness of Small Lung Nodules

by Xia Zou, Feng Yao, Fang Yang, Fang Zhang, Zhijue Xu, Jingjing Shi, Atsushi Kuno, Heng Zhao and Yan Zhang

Molecules 2020, 25(1), 28; https://doi.org/10.3390/molecules25010028 - 20 Dec 2019

Cited by 13 | Viewed by 3261

Abstract

Preoperative assessment of tumor invasiveness is essential to avoid overtreatment for patients with small-sized ground-glass nodules (GGNs) of 10 mm or less in diameter. However, it is difficult to determine the pathological state by computed tomography (CT) examination alone. Aberrant glycans has emerged [...] Read more.

Preoperative assessment of tumor invasiveness is essential to avoid overtreatment for patients with small-sized ground-glass nodules (GGNs) of 10 mm or less in diameter. However, it is difficult to determine the pathological state by computed tomography (CT) examination alone. Aberrant glycans has emerged as a tool to identify novel potential disease biomarkers. In this study, we used a lectin microarray-based strategy to investigate whether glycosylation changes in plasma immunoglobulin G (IgG) provide additional information about the invasiveness of small GGNs before surgery. Two independent cohorts (discovery set, n = 92; test set, n = 210) of GGN patients were used. Five of 45 lectins (Sambucus nigra agglutinin, SNA; Datura stramonium agglutinin, DSA; Galanthus nivalis agglutinin, GNA; Euonymus europaeus lectin, EEL; and Vicia villosa agglutinin, VVA) were identified as independent factors associated with pathological invasiveness of small GGNs (p < 0.01). Receiver-operating characteristic (ROC) curve analysis indicated the combination of these five lectins could significantly improve the accuracy of CT in diagnosing invasive GGNs, with an area under the curve (AUC) of 0.792 (p < 0.001), a sensitivity of 74.6%, and specificity of 74.4%, which was superior to current clinical biomarkers. These results suggest that the multilectin assay based on plasma IgG glycosylation may be a useful in vitro complementary test to enhance preoperative determination of the invasiveness of GGNs and guide surgeons to select proper clinical management to avoid overtreatment. Full article

(This article belongs to the Special Issue Lectins: From Biochemical and Structural Studies to Biotechnological and Biomedical Applications)

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15 pages, 2505 KiB

Open AccessArticle

Binding of Gold(III) Porphyrin by the Pro-metastatic Regulatory Protein Human Galectin-3

by Vanya Bogoeva, Miroslav Rangelov, Nadezhda Todorova, Annie Lambert, Clarisse Bridot, Anna Yordanova, Goedele Roos, Cyrille Grandjean and Julie Bouckaert

Molecules 2019, 24(24), 4561; https://doi.org/10.3390/molecules24244561 - 12 Dec 2019

Cited by 5 | Viewed by 2829

Abstract

Gold(III) porphyrin presents an attractive alternative to the use of, for example, cisplatin in chemotherapy. However, approaches that allow to selectively target cancer cells are highly sought. Many plant and mammalian lectins have been shown to bind oligosaccharide sequences of the aberrant glycosylation [...] Read more.

Gold(III) porphyrin presents an attractive alternative to the use of, for example, cisplatin in chemotherapy. However, approaches that allow to selectively target cancer cells are highly sought. Many plant and mammalian lectins have been shown to bind oligosaccharide sequences of the aberrant glycosylation pattern found on cancerous tumors. For example human galectin-3, of the galectin family specific for β-galactoside, is overexpressed in the extracellular matrix of tumorigenous and metastatic tissues. We searched for non-carbohydrate ligands for galectin-3 that can guide a cytotoxic drug to the cancer cells by maintaining its affinity for tumor associated carbohydrate antigens. Previous findings showed that zinc tetrasulfonatophenylporphyrin can bind galectin-3 with sub-micromolar affinity without disturbing lactose binding. Gold(III) porphyrin is not only cytotoxic to cancer cells, it knows also a potential application as photosensitiser in photodynamic therapy. We investigated the binding of gold(III) porphyrin to galectin-3 using different biophysical interaction techniques and demonstrated a low micromolar affinity of human galectin-3 for the cytotoxic compound. Co-crystallization attempts in order to understand the binding mode of gold porphyrin to galectin-3 failed, but molecular docking emphasized a highly populated secondary binding site that does not hinder lactose or Thomsen Friendenreich disaccharide binding. This suggests that gold(III) porphyrin might significantly enhance its concentration and delivery to cancer cells by binding to human galectin-3 that keeps its orientation towards tumor associated carbohydrate antigens. Full article

(This article belongs to the Special Issue Lectins: From Biochemical and Structural Studies to Biotechnological and Biomedical Applications)

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15 pages, 2414 KiB

Open AccessArticle

3-Substituted 1-Naphthamidomethyl-C-galactosyls Interact with Two Unique Sub-Sites for High-Affinity and High-Selectivity Inhibition of Galectin-3

by Alexander Dahlqvist, Santanu Mandal, Kristoffer Peterson, Maria Håkansson, Derek T. Logan, Fredrik R. Zetterberg, Hakon Leffler and Ulf J. Nilsson

Molecules 2019, 24(24), 4554; https://doi.org/10.3390/molecules24244554 - 12 Dec 2019

Cited by 5 | Viewed by 3169

Abstract

The galectins are a family of galactose-binding proteins playing key roles in inflammatory processes and cancer. However, they are structurally very closely related, and discovery of highly selective inhibitors is challenging. In this work, we report the design of novel inhibitors binding to [...] Read more.

The galectins are a family of galactose-binding proteins playing key roles in inflammatory processes and cancer. However, they are structurally very closely related, and discovery of highly selective inhibitors is challenging. In this work, we report the design of novel inhibitors binding to a subsite unique to galectin-3, which confers both high selectivity and affinity towards galectin-3. Olefin cross metathesis between allyl β-C-galactopyranosyl and 1-vinylnaphthalenes or acylation of aminomethyl β-C-galactopyranosyl with 1-naphthoic acid derivatives gave C-galactopyranosyls carrying 1-naphthamide structural elements that interacted favorably with a galectin-3 unique subsite according to molecular modeling and X-ray structural analysis of two inhibitor-galectin-3 complexes. Affinities were down to sub-µM and selectivities over galectin-1, 2, 4 N-terminal domain, 4 C-terminal domain, 7, 8 N-terminal domain, 9 N-terminal domain, and 9 C-terminal domain were high. These results show that high affinity and selectivity for a single galectin can be achieved by targeting unique subsites, which holds promise for further development of small and selective galectin inhibitors. Full article

(This article belongs to the Special Issue Lectins: From Biochemical and Structural Studies to Biotechnological and Biomedical Applications)

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20 pages, 3911 KiB

Open AccessArticle

Lectin PLL3, a Novel Monomeric Member of the Seven-Bladed β-Propeller Lectin Family

by Lukáš Faltinek, Eva Fujdiarová, Filip Melicher, Josef Houser, Martina Kašáková, Nikolay Kondakov, Leonid Kononov, Kamil Parkan, Sébastien Vidal and Michaela Wimmerová

Molecules 2019, 24(24), 4540; https://doi.org/10.3390/molecules24244540 - 11 Dec 2019

Cited by 2 | Viewed by 3665

Abstract

The Photorhabdus species is a Gram-negative bacteria of the family Morganellaceae that is known for its mutualistic relationship with Heterorhabditis nematodes and pathogenicity toward insects. This study is focused on the characterization of the recombinant lectin PLL3 with an origin in P. laumondii [...] Read more.

The Photorhabdus species is a Gram-negative bacteria of the family Morganellaceae that is known for its mutualistic relationship with Heterorhabditis nematodes and pathogenicity toward insects. This study is focused on the characterization of the recombinant lectin PLL3 with an origin in P. laumondii subsp. laumondii. PLL3 belongs to the PLL family of lectins with a seven-bladed β-propeller fold. The binding properties of PLL3 were tested by hemagglutination assay, glycan array, isothermal titration calorimetry, and surface plasmon resonance, and its structure was determined by X-ray crystallography. Obtained data revealed that PLL3 binds similar carbohydrates to those that the other PLL family members bind, with some differences in the binding properties. PLL3 exhibited the highest affinity toward l-fucose and its derivatives but was also able to interact with O-methylated glycans and other ligands. Unlike the other members of this family, PLL3 was discovered to be a monomer, which might correspond to a weaker avidity effect compared to homologous lectins. Based on the similarity to the related lectins and their proposed biological function, PLL3 might accompany them during the interaction of P. laumondii with both the nematode partner and the insect host. Full article

(This article belongs to the Special Issue Lectins: From Biochemical and Structural Studies to Biotechnological and Biomedical Applications)

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16 pages, 1930 KiB

Open AccessArticle

Lectin-Based Method for Deciphering Human Milk IgG Sialylation

by Jolanta Lis-Kuberka, Barbara Królak-Olejnik, Marta Berghausen-Mazur and Magdalena Orczyk-Pawiłowicz

Molecules 2019, 24(20), 3797; https://doi.org/10.3390/molecules24203797 - 22 Oct 2019

Cited by 9 | Viewed by 3149

Abstract

In light of the immunoprotective function of human milk and the incontestable impact of IgG glycosylation on its immune functions, characterization of the sialylation profile of human milk IgG is needed. Lectins as a molecular probe were applied in lectin-IgG-ELISA to analyze the [...] Read more.

In light of the immunoprotective function of human milk and the incontestable impact of IgG glycosylation on its immune functions, characterization of the sialylation profile of human milk IgG is needed. Lectins as a molecular probe were applied in lectin-IgG-ELISA to analyze the sialylation and galactosylation pattern of skim milk IgG of mothers who delivered at term and prematurely. Well-defined biotinylated lectins were used: Maackia amurensis II (MAA II), Sambucus nigra (SNA), Ricinus communis I (RCA I), and Griffonia simplicifolia II (GSL II) specific to α2,3-Neu5Ac, α2,6-Neu5Ac, Gal(β1,4)GlcNAc, and agalactosylated glycans, respectively. The sialylation pattern of milk IgG differs qualitatively and quantitatively from maternal plasma IgG and is related to lactation stage and perinatal risk factors. Expression of MAA-, SNA-, and GSL-reactive glycotopes on term milk IgG showed a positive correlation with milk maturation from days 1 to 55. Preterm birth was associated with an increase of MAA-reactive and a decrease of RCA-reactive IgG glycotopes. Moreover, higher SNA- and GSL-reactive and lower RCA-reactive glycoform levels of milk IgG were associated with infection of lactating mothers. Application of a specific and simple method, lectin-IgG-ELISA, reveals the sialylation pattern of milk IgG over milk maturation. However, further investigations are needed in this area. Full article

(This article belongs to the Special Issue Lectins: From Biochemical and Structural Studies to Biotechnological and Biomedical Applications)

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11 pages, 2191 KiB

Open AccessArticle

LM-GlycomeAtlas Ver. 1.0: A Novel Visualization Tool for Lectin Microarray-Based Glycomic Profiles of Mouse Tissue Sections

by Chiaki Nagai-Okatani, Kiyoko F Aoki-Kinoshita, Shuichi Kakuda, Misugi Nagai, Kozue Hagiwara, Katsue Kiyohara, Noriaki Fujita, Yoshinori Suzuki, Takashi Sato, Kiyohiko Angata and Atsushi Kuno

Molecules 2019, 24(16), 2962; https://doi.org/10.3390/molecules24162962 - 15 Aug 2019

Cited by 7 | Viewed by 3541

Abstract

For the effective discovery of the biological roles and disease-specific alterations concerning protein glycosylation in tissue samples, it is important to know beforehand the quantitative and qualitative variations of glycan structures expressed in various types of cells, sites, and tissues. To this end, [...] Read more.

For the effective discovery of the biological roles and disease-specific alterations concerning protein glycosylation in tissue samples, it is important to know beforehand the quantitative and qualitative variations of glycan structures expressed in various types of cells, sites, and tissues. To this end, we used laser microdissection-assisted lectin microarray (LMA) to establish a simple and reproducible method for high-throughput and in-depth glycomic profiling of formalin-fixed paraffin-embedded tissue sections. Using this “tissue glycome mapping” approach, we present 234 glycomic profiling data obtained from nine tissue sections (pancreas, heart, lung, thymus, gallbladder, stomach, small intestine, colon, and skin) of two 8-week-old male C57BL/6J mice. We provided this LMA-based dataset in the similar interface as that of GlycomeAtlas, a previously developed tool for mass spectrometry-based tissue glycomic profiling, allowing easy comparison of the two types of data. This online tool, called “LM-GlycomeAtlas”, allows users to visualize the LMA-based tissue glycomic profiling data associated with the sample information as an atlas. Since the present dataset allows the comparison of glycomic profiles, it will facilitate the evaluation of site- and tissue-specific glycosylation patterns. Taking advantage of its extensibility, this tool will continue to be updated with the expansion of deposited data. Full article

(This article belongs to the Special Issue Lectins: From Biochemical and Structural Studies to Biotechnological and Biomedical Applications)

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Review

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10 pages, 10490 KiB

Open AccessReview

CNL–Clitocybe nebularis Lectin—The Fungal GalNAcβ1-4GlcNAc-Binding Lectin

by Jerica Sabotič and Janko Kos

Molecules 2019, 24(23), 4204; https://doi.org/10.3390/molecules24234204 - 20 Nov 2019

Cited by 8 | Viewed by 3288

Abstract

Clitocybe nebularis lectin (CNL) is present in fruiting bodies of clouded agaric along with several similar isolectins that are all small and stable proteins. It is a beta-trefoil type lectin forming homodimers that are essential for its functionality. It binds specifically N, [...] Read more.

Clitocybe nebularis lectin (CNL) is present in fruiting bodies of clouded agaric along with several similar isolectins that are all small and stable proteins. It is a beta-trefoil type lectin forming homodimers that are essential for its functionality. It binds specifically N,N′-diacetyllactosediamine (GalNAcβ1-4GlcNAc, LacDiNac) and human blood group A determinant-containing glycan epitopes. Its most probable function is to defend fruiting bodies against predators and parasites. In addition, an endogenous regulatory function is possible for CNL, as indicated by its interaction with fungal protease inhibitors sharing the beta-trefoil fold. CNL is toxic to insects, nematodes and amoebae, as well as to leukemic T-cell lines. Bivalent carbohydrate binding is essential for the toxicity of CNL, against both invertebrates and cancer-derived cell lines. In addition, CNL exhibits potent immunostimulation of human dendritic cells, resulting in a strong T helper cell type 1 response. Based on its unique characteristics, CNL is a promising candidate for applications in human and veterinary medicine as well as in agriculture, for plant protection. Full article

(This article belongs to the Special Issue Lectins: From Biochemical and Structural Studies to Biotechnological and Biomedical Applications)

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