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Molecular Recognition of Carbohydrates

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2017) | Viewed by 54659

Special Issue Editors

Chemical and Physical Biology, Centro de Investigaciones Biológicas, CIB-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
Interests: carbohydrates; molecular recognition; NMR
1. CIC bioGUNE, Bizkaia Technology Park, Building 800, 48160 Derio, Spain
2. Ikerbasque, Basque Foundation for Science, Maria López de Haro 3, 48013 Bilbao, Spain
Interests: NMR; molecular recognition; glycans; protein-ligand interactions; chemical biology; medicinal chemistry; infectious diseases; cancer; rare diseases; metabolomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Carbohydrates are among the most ubiquitous and complex types of biomolecules in nature. Although they are secondary gene products, and look like very simple molecules in terms of chemical functional groups (polyhydroxylated molecules with a formal carbonyl group), they support an astonishing capacity of carrying biological information, conforming to the so-called “glycan code”. The possibilities of diversity for their oligomeric structures (stereochemistry, branching, and secondary modifications) overwhelm those exerted by the other two key biomolecules, nucleic acids and proteins.

Carbohydrates play a very important role in intra- and intercellular molecular recognition events that trigger a variety of physiological and pathological events (glycoprotein fate and stability, fertilization, immunological responses, inflammation, cell defense or infection, cancer, etc).

Therefore, knowledge of their precise chemical structure with the maximum resolution possible, and access to key information on their interaction processes with different entities, such as lectins, enzymes, and antibodies, are essential for the understanding of many vital processes, as well as for opening the possibility of their modulation. To this aim, multidisciplinary research strategies (design and synthesis of natural glycans and their glycomimetics, development of glycoarrays and glyconanomaterials, physico-chemical characterization, NMR and X-ray structural determination, molecular modeling, biotechnological production, and cell biology protocols) are in continuous expansion in the field of glycosciences.

Prof. Francisco Javier Cañada
Prof. Jesus Jimenez-Barbero
Guest Editors

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Keywords

  • Glycosciences
  • Molecular recognition
  • Carbohydrate-protein interactions
  • Glycomimetics
  • Glycoarrays
  • Glycomics
  • Carbohydrate structure
  • Carbohydrate synthesis
  • Glyconanostructures (glyconanoparticles, glycan dendrimers)
  • NMR

Published Papers (9 papers)

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Research

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13 pages, 1538 KiB  
Article
A Combined NMR-Computational Study of the Interaction between Influenza Virus Hemagglutinin and Sialic Derivatives from Human and Avian Receptors on the Surface of Transfected Cells
by Francesca Vasile, Maddalena Panigada, Antonio Siccardi, Donatella Potenza and Guido Tiana
Int. J. Mol. Sci. 2018, 19(5), 1267; https://doi.org/10.3390/ijms19051267 - 24 Apr 2018
Cited by 13 | Viewed by 4451
Abstract
The development of small-molecule inhibitors of influenza virus Hemagglutinin could be relevant to the opposition of the diffusion of new pandemic viruses. In this work, we made use of Nuclear Magnetic Resonance (NMR) spectroscopy to study the interaction between two derivatives of sialic [...] Read more.
The development of small-molecule inhibitors of influenza virus Hemagglutinin could be relevant to the opposition of the diffusion of new pandemic viruses. In this work, we made use of Nuclear Magnetic Resonance (NMR) spectroscopy to study the interaction between two derivatives of sialic acid, Neu5Ac-α-(2,6)-Gal-β-(1–4)-GlcNAc and Neu5Ac-α-(2,3)-Gal-β-(1–4)-GlcNAc, and hemagglutinin directly expressed on the surface of recombinant human cells. We analyzed the interaction of these trisaccharides with 293T cells transfected with the H5 and H1 variants of hemagglutinin, which thus retain their native trimeric conformation in such a realistic environment. By exploiting the magnetization transfer between the protein and the ligand, we obtained evidence of the binding event, and identified the epitope. We analyzed the conformational features of the glycans with an approach combining NMR spectroscopy and data-driven molecular dynamics simulations, thus obtaining useful information for an efficient drug design. Full article
(This article belongs to the Special Issue Molecular Recognition of Carbohydrates)
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20 pages, 10767 KiB  
Article
Lectin-Binding Specificity of the Fertilization-Relevant Protein PDC-109 by Means of Surface Plasmon Resonance and Carbohydrate REcognition Domain EXcision-Mass Spectrometry
by Sira Defaus, Manuel Avilés, David Andreu and Ricardo Gutiérrez-Gallego
Int. J. Mol. Sci. 2018, 19(4), 1076; https://doi.org/10.3390/ijms19041076 - 04 Apr 2018
Cited by 6 | Viewed by 3612
Abstract
Seminal plasma proteins are relevant for sperm functionality and some appear responsible for establishing sperm interactions with the various environments along the female genital tract towards the oocyte. In recent years, research has focused on characterizing the role of these proteins in the [...] Read more.
Seminal plasma proteins are relevant for sperm functionality and some appear responsible for establishing sperm interactions with the various environments along the female genital tract towards the oocyte. In recent years, research has focused on characterizing the role of these proteins in the context of reproductive biology, fertility diagnostics and treatment of related problems. Herein, we focus on the main protein of bovine seminal plasma, PDC-109 (BSP-A1/-A2), which by virtue of its lectin properties is involved in fertilization. By means of surface plasmon resonance, the interaction of PDC-109 with a panel of the most relevant glycosidic epitopes of mammals has been qualitatively and quantitatively characterized, and a higher affinity for carbohydrates containing fucose has been observed, in line with previous studies. Additionally, using the orthogonal technique of Carbohydrate REcognition Domain EXcision-Mass Spectrometry (CREDEX-MS), the recognition domain of the interaction complexes between PDC-109 and all fucosylated disaccharides [(Fuc-α1,(3,4,6)-GlcNAc)] has been defined, revealing the specific glycotope and the peptide domain likely to act as the PDC-109 carbohydrate binding site. Full article
(This article belongs to the Special Issue Molecular Recognition of Carbohydrates)
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4129 KiB  
Article
Glycosaminoglycan-Mediated Downstream Signaling of CXCL8 Binding to Endothelial Cells
by Rupert Derler, Bernd Gesslbauer, Corinna Weber, Elisabeth Strutzmann, Ingrid Miller and Andreas Kungl
Int. J. Mol. Sci. 2017, 18(12), 2605; https://doi.org/10.3390/ijms18122605 - 04 Dec 2017
Cited by 20 | Viewed by 4338
Abstract
The recruitment of leukocytes, mediated by endothelium bound chemokine gradients, is a vital process in inflammation. The highly negatively charged, unbranched polysaccharide family of glycosaminoglycans (GAGs), such as heparan sulfate and chondroitin sulfate mediate chemokine immobilization. Specifically the binding of CXCL8 (interleukin 8) [...] Read more.
The recruitment of leukocytes, mediated by endothelium bound chemokine gradients, is a vital process in inflammation. The highly negatively charged, unbranched polysaccharide family of glycosaminoglycans (GAGs), such as heparan sulfate and chondroitin sulfate mediate chemokine immobilization. Specifically the binding of CXCL8 (interleukin 8) to GAGs on endothelial cell surfaces is known to regulate neutrophil recruitment. Currently, it is not clear if binding of CXCL8 to GAGs leads to endothelial downstream signaling in addition to the typical CXCR1/CXCR2 (C-X-C motif chemokine receptor 1 and 2)-mediated signaling which activates neutrophils. Here we have investigated the changes in protein expression of human microvascular endothelial cells induced by CXCL8. Tumor necrosis factor alpha (TNFα) stimulation was used to mimic an inflammatory state which allowed us to identify syndecan-4 (SDC4) as the potential proteoglycan co-receptor of CXCL8 by gene array, real-time PCR and flow cytometry experiments. Enzymatic GAG depolymerization via heparinase III and chondroitinase ABC was used to emulate the effect of glycocalyx remodeling on CXCL8-induced endothelial downstream signaling. Proteomic analyses showed changes in the expression pattern of a number of endothelial proteins such as Zyxin and Caldesmon involved in cytoskeletal organization, cell adhesion and cell mobility. These results demonstrate for the first time a potential role of GAG-mediated endothelial downstream signaling in addition to the well-known CXCL8-CXCR1/CXCR2 signaling pathways in neutrophils. Full article
(This article belongs to the Special Issue Molecular Recognition of Carbohydrates)
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5355 KiB  
Article
De Novo Assembly and Analysis of Polygonatum sibiricum Transcriptome and Identification of Genes Involved in Polysaccharide Biosynthesis
by Shiqiang Wang, Bin Wang, Wenping Hua, Junfeng Niu, Kaikai Dang, Yi Qiang and Zhezhi Wang
Int. J. Mol. Sci. 2017, 18(9), 1950; https://doi.org/10.3390/ijms18091950 - 12 Sep 2017
Cited by 44 | Viewed by 4928
Abstract
Polygonatum sibiricum polysaccharides (PSPs) are used to improve immunity, alleviate dryness, promote the secretion of fluids, and quench thirst. However, the PSP biosynthetic pathway is largely unknown. Understanding the genetic background will help delineate that pathway at the molecular level so that researchers [...] Read more.
Polygonatum sibiricum polysaccharides (PSPs) are used to improve immunity, alleviate dryness, promote the secretion of fluids, and quench thirst. However, the PSP biosynthetic pathway is largely unknown. Understanding the genetic background will help delineate that pathway at the molecular level so that researchers can develop better conservation strategies. After comparing the PSP contents among several different P. sibiricum germplasms, we selected two groups with the largest contrasts in contents and subjected them to HiSeq2500 transcriptome sequencing to identify the candidate genes involved in PSP biosynthesis. In all, 20 kinds of enzyme-encoding genes were related to PSP biosynthesis. The polysaccharide content was positively correlated with the expression patterns of β-fructofuranosidase (sacA), fructokinase (scrK), UDP-glucose 4-epimerase (GALE), Mannose-1-phosphate guanylyltransferase (GMPP), and UDP-glucose 6-dehydrogenase (UGDH), but negatively correlated with the expression of Hexokinase (HK). Through qRT-PCR validation and comprehensive analysis, we determined that sacA, HK, and GMPP are key genes for enzymes within the PSP metabolic pathway in P. sibiricum. Our results provide a public transcriptome dataset for this species and an outline of pathways for the production of polysaccharides in medicinal plants. They also present more information about the PSP biosynthesis pathway at the molecular level in P. sibiricum and lay the foundation for subsequent research of gene functions. Full article
(This article belongs to the Special Issue Molecular Recognition of Carbohydrates)
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5520 KiB  
Article
Interactions between a Heparin Trisaccharide Library and FGF-1 Analyzed by NMR Methods
by María José García-Jiménez, Sergio Gil-Caballero, Ángeles Canales, Jesús Jiménez-Barbero, José L. De Paz and Pedro M. Nieto
Int. J. Mol. Sci. 2017, 18(6), 1293; https://doi.org/10.3390/ijms18061293 - 17 Jun 2017
Cited by 12 | Viewed by 4857
Abstract
FGF-1 is a potent mitogen that, by interacting simultaneously with Heparan Sulfate Glycosaminoglycan HSGAG and the extracellular domains of its membrane receptor (FGFR), generates an intracellular signal that finally leads to cell division. The overall structure of the ternary complex Heparin:FGF-1:FGFR has been [...] Read more.
FGF-1 is a potent mitogen that, by interacting simultaneously with Heparan Sulfate Glycosaminoglycan HSGAG and the extracellular domains of its membrane receptor (FGFR), generates an intracellular signal that finally leads to cell division. The overall structure of the ternary complex Heparin:FGF-1:FGFR has been finally elucidated after some controversy and the interactions within the ternary complex have been deeply described. However, since the structure of the ternary complex was described, not much attention has been given to the molecular basis of the interaction between FGF-1 and the HSGAG. It is known that within the complex, the carbohydrate maintains the same helical structure of free heparin that leads to sulfate groups directed towards opposite directions along the molecular axis. The precise role of single individual interactions remains unclear, as sliding and/or rotating of the saccharide along the binding pocket are possibilities difficult to discard. The HSGAG binding pocket can be subdivided into two regions, the main one can accommodate a trisaccharide, while the other binds a disaccharide. We have studied and analyzed the interaction between FGF-1 and a library of trisaccharides by STD-NMR and selective longitudinal relaxation rates. The library of trisaccharides corresponds to the heparin backbone and it has been designed to interact with the main subsite of the protein. Full article
(This article belongs to the Special Issue Molecular Recognition of Carbohydrates)
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7256 KiB  
Article
Crystallization of Galectin-8 Linker Reveals Intricate Relationship between the N-terminal Tail and the Linker
by Yunlong Si, Yue Wang, Jin Gao, Chenyang Song, Shiqiong Feng, Yifa Zhou, Guihua Tai and Jiyong Su
Int. J. Mol. Sci. 2016, 17(12), 2088; https://doi.org/10.3390/ijms17122088 - 12 Dec 2016
Cited by 21 | Viewed by 4670
Abstract
Galectin-8 (Gal-8) plays a significant role in normal immunological function as well as in cancer. This lectin contains two carbohydrate recognition domains (CRD) connected by a peptide linker. The N-terminal CRD determines ligand binding specificity, whereas the linker has been proposed to regulate [...] Read more.
Galectin-8 (Gal-8) plays a significant role in normal immunological function as well as in cancer. This lectin contains two carbohydrate recognition domains (CRD) connected by a peptide linker. The N-terminal CRD determines ligand binding specificity, whereas the linker has been proposed to regulate overall Gal-8 function, including multimerization and biological activity. Here, we crystallized the Gal-8 N-terminal CRD with the peptide linker using a crystallization condition that contains Ni2+. The Ni2+ ion was found to be complexed between two CRDs via crystal packing contacts. The coordination between Ni2+ and Asp25 plays an indirect role in determining the structure of β-strand F0 and in influencing the linker conformation which could not be defined due to its dynamic nature. The linker was also shortened in situ and crystallized under a different condition, leading to a higher resolution structure refined to 1.08 Å. This crystal structure allowed definition of a short portion of the linker interacting with the Gal-8 N-terminal tail via ionic interactions and hydrogen bonds. Observation of two Gal-8 N-terminal CRD structures implies that the N-terminal tail and the linker may influence each other’s conformation. In addition, under specific crystallization conditions, glycerol could replace lactose and was observed at the carbohydrate binding site. However, glycerol did not show inhibition activity in hemagglutination assay. Full article
(This article belongs to the Special Issue Molecular Recognition of Carbohydrates)
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Review

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20 pages, 770 KiB  
Review
Pathogen-Derived Carbohydrate Recognition in Molluscs Immune Defense
by Weilin Wang, Xiaorui Song, Lingling Wang and Linsheng Song
Int. J. Mol. Sci. 2018, 19(3), 721; https://doi.org/10.3390/ijms19030721 - 03 Mar 2018
Cited by 75 | Viewed by 6429
Abstract
Self-nonself discrimination is a common theme for all of the organisms in different evolutionary branches, which is also the most fundamental step for host immune protection. Plenty of pattern recognition receptors (PRRs) with great diversity have been identified from different organisms to recognize [...] Read more.
Self-nonself discrimination is a common theme for all of the organisms in different evolutionary branches, which is also the most fundamental step for host immune protection. Plenty of pattern recognition receptors (PRRs) with great diversity have been identified from different organisms to recognize various pathogen-associated molecular patterns (PAMPs) in the last two decades, depicting a complicated scene of host-pathogen interaction. However, the detailed mechanism of the complicate PAMPs–PRRs interactions at the contacting interface between pathogens and hosts is still not well understood. All of the cells are coated by glycosylation complex and thick carbohydrates layer. The different polysaccharides in extracellular matrix of pathogen-host are important for nonself recognition of most organisms. Coincidentally, massive expansion of PRRs, majority of which contain recognition domains of Ig, leucine-rich repeat (LRR), C-type lectin (CTL), C1q and scavenger receptor (SR), have been annotated and identified in invertebrates by screening the available genomic sequence. The phylum Mollusca is one of the largest groups in the animal kingdom with abundant biodiversity providing plenty of solutions about pathogen recognition and immune protection, which might offer a suitable model to figure out the common rules of immune recognition mechanism. The present review summarizes the diverse PRRs and common elements of various PAMPs, especially focusing on the structural and functional characteristics of canonical carbohydrate recognition proteins and some novel proteins functioning in molluscan immune defense system, with the objective to provide new ideas about the immune recognition mechanisms. Full article
(This article belongs to the Special Issue Molecular Recognition of Carbohydrates)
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30 pages, 18158 KiB  
Review
Substrate Recognition and Specificity of Chitin Deacetylases and Related Family 4 Carbohydrate Esterases
by Hugo Aragunde, Xevi Biarnés and Antoni Planas
Int. J. Mol. Sci. 2018, 19(2), 412; https://doi.org/10.3390/ijms19020412 - 30 Jan 2018
Cited by 51 | Viewed by 6664
Abstract
Carbohydrate esterases family 4 (CE4 enzymes) includes chitin and peptidoglycan deacetylases, acetylxylan esterases, and poly-N-acetylglucosamine deacetylases that act on structural polysaccharides, altering their physicochemical properties, and participating in diverse biological functions. Chitin and peptidoglycan deacetylases are not only involved in cell [...] Read more.
Carbohydrate esterases family 4 (CE4 enzymes) includes chitin and peptidoglycan deacetylases, acetylxylan esterases, and poly-N-acetylglucosamine deacetylases that act on structural polysaccharides, altering their physicochemical properties, and participating in diverse biological functions. Chitin and peptidoglycan deacetylases are not only involved in cell wall morphogenesis and remodeling in fungi and bacteria, but they are also used by pathogenic microorganisms to evade host defense mechanisms. Likewise, biofilm formation in bacteria requires partial deacetylation of extracellular polysaccharides mediated by poly-N-acetylglucosamine deacetylases. Such biological functions make these enzymes attractive targets for drug design against pathogenic fungi and bacteria. On the other side, acetylxylan esterases deacetylate plant cell wall complex xylans to make them accessible to hydrolases, making them attractive biocatalysts for biomass utilization. CE4 family members are metal-dependent hydrolases. They are highly specific for their particular substrates, and show diverse modes of action, exhibiting either processive, multiple attack, or patterned deacetylation mechanisms. However, the determinants of substrate specificity remain poorly understood. Here, we review the current knowledge on the structure, activity, and specificity of CE4 enzymes, focusing on chitin deacetylases and related enzymes active on N-acetylglucosamine-containing oligo and polysaccharides. Full article
(This article belongs to the Special Issue Molecular Recognition of Carbohydrates)
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5355 KiB  
Review
The Role of Carbohydrates in the Lipopolysaccharide (LPS)/Toll-Like Receptor 4 (TLR4) Signalling
by Florent Cochet and Francesco Peri
Int. J. Mol. Sci. 2017, 18(11), 2318; https://doi.org/10.3390/ijms18112318 - 03 Nov 2017
Cited by 118 | Viewed by 13286
Abstract
The interactions between sugar-containing molecules from the bacteria cell wall and pattern recognition receptors (PRR) on the plasma membrane or cytosol of specialized host cells are the first molecular events required for the activation of higher animal’s immune response and inflammation. This review [...] Read more.
The interactions between sugar-containing molecules from the bacteria cell wall and pattern recognition receptors (PRR) on the plasma membrane or cytosol of specialized host cells are the first molecular events required for the activation of higher animal’s immune response and inflammation. This review focuses on the role of carbohydrates of bacterial endotoxin (lipopolysaccharide, LPS, lipooligosaccharide, LOS, and lipid A), in the interaction with the host Toll-like receptor 4/myeloid differentiation factor 2 (TLR4/MD-2) complex. The lipid chains and the phosphorylated disaccharide core of lipid A moiety are responsible for the TLR4 agonist action of LPS, and the specific interaction between MD-2, TLR4, and lipid A are key to the formation of the activated complex (TLR4/MD-2/LPS)2, which starts intracellular signalling leading to nuclear factors activation and to production of inflammatory cytokines. Subtle chemical variations in the lipid and sugar parts of lipid A cause dramatic changes in endotoxin activity and are also responsible for the switch from TLR4 agonism to antagonism. While the lipid A pharmacophore has been studied in detail and its structure-activity relationship is known, the contribution of core saccharides 3-deoxy-d-manno-octulosonic acid (Kdo) and heptosyl-2-keto-3-deoxy-octulosonate (Hep) to TLR4/MD-2 binding and activation by LPS and LOS has been investigated less extensively. This review focuses on the role of lipid A, but also of Kdo and Hep sugars in LPS/TLR4 signalling. Full article
(This article belongs to the Special Issue Molecular Recognition of Carbohydrates)
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