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Structural and Functional Approach to the Glycan Diversity

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 43904

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Dr. Jun-ichi Furukawa

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Guest Editor

Department of Advanced Clinical Glycobiology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
Interests: glycomics total glycome analysis; analytical technique; sialyl-linkage specific derivatization

Dr. Hiroshi Manya

E-Mail Website
Guest Editor

Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan
Interests: glycan biosynthesis; aging; age-rerated disorders; O-mannosyl glycan; neuro-muscular function

Special Issue Information

Dear Colleagues,

Glycosylation is one of the most important modifications of proteins and lipids. These glycoconjugates on proteins and lipids play important roles in various biological events such as molecular interaction, cell recognition, virus infection, etc. Contrary to proteins and mRNA, which are encoded directly in DNA by the central dogma, glycoconjugates are not direct products of DNA. Glycan biosynthesis proceeds via complex pathway involving hundreds of enzymatic reactions and is susceptible to environmental factors. Structures of glycoconjugates are known to change depending on the cell culture conditions, the differentiation of cells, aging, and clinical stage. Recent researches have revealed that the glycan heterogeneity and diversity affect the biological functions of proteins and lipids. We focus on the biological events depending on glycan alterations by various approaches such as biological chemistry, analytical chemistry, cell biology, and bioinformatics. This Special Issue calls for original research, reviews, and perspectives that address the progress and current knowledge on glycobiology and glycotechnology by structural and functional approaches.

Dr. Jun-ichi Furukawa
Dr. Hiroshi Manya
Guest Editors

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Keywords

glycoconjugates as biomolecules
glycobiology
glycomic analysis
glyco-related bioinformatics
glycans in disease
glycan structure/function relationship

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Published Papers (9 papers)

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Research

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13 pages, 9154 KiB

Open AccessArticle

Glycan Epitopes on 201B7 Human-Induced Pluripotent Stem Cells Using R-10G and R-17F Marker Antibodies

by Yuko Nagai, Hiromi Nakao, Aya Kojima, Yuka Komatsubara, Yuki Ohta, Nana Kawasaki, Nobuko Kawasaki, Hidenao Toyoda and Toshisuke Kawasaki

Biomolecules 2021, 11(4), 508; https://doi.org/10.3390/biom11040508 - 29 Mar 2021

Cited by 4 | Viewed by 2525

Abstract

We developed two human-induced pluripotent stem cell (hiPSC)/human embryonic stem cell (hESC)-specific glycan-recognizing mouse antibodies, R-10G and R-17F, using the Tic (JCRB1331) hiPSC line as an antigen. R-10G recognizes a low-sulfate keratan sulfate, and R-17F recognizes lacto-N-fucopentaose-1. To evaluate the general characteristics of stem cell glycans, we investigated the hiPSC line 201B7 (HPS0063), a prototype iPSC line. Using an R-10G affinity column, an R-10G-binding protein was isolated from 201B7 cells. The protein yielded a single but very broad band from 480 to 1236 kDa by blue native gel electrophoresis. After trypsin digestion, the protein was identified as podocalyxin by liquid chromatography/mass spectrometry. According to Western blotting, the protein reacted with R-10G and R-17F. The R-10G-positive band was resistant to digestion with glycan-degrading enzymes, including peptide N-glycanase, but the intensity of the band was decreased significantly by digestion with keratanase, keratanase II, and endo-β-galactosidase, suggesting the R-10G epitope to be a keratan sulfate. These results suggest that keratan sulfate-type epitopes are shared by hiPSCs. However, the keratan sulfate from 201B7 cells contained a polylactosamine disaccharide unit (Galβ1-4GlcNAc) at a significant frequency, whereas that from Tic cells consisted mostly of keratan sulfate disaccharide units (Galβ1-4GlcNAc(6S)). In addition, the abundance of the R-10G epitope was significantly lower in 201B7 cells than in Tic cells. Full article

(This article belongs to the Special Issue Structural and Functional Approach to the Glycan Diversity)

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15 pages, 3353 KiB

Open AccessArticle

Alterations of Glycosphingolipid Glycans and Chondrogenic Markers during Differentiation of Human Induced Pluripotent Stem Cells into Chondrocytes

by Liang Xu, Hisatoshi Hanamatsu, Kentaro Homan, Tomohiro Onodera, Takuji Miyazaki, Jun-ichi Furukawa, Kazutoshi Hontani, Yuan Tian, Rikiya Baba and Norimasa Iwasaki

Biomolecules 2020, 10(12), 1622; https://doi.org/10.3390/biom10121622 - 1 Dec 2020

Cited by 9 | Viewed by 2935

Abstract

Due to the limited intrinsic healing potential of cartilage, injury to this tissue may lead to osteoarthritis. Human induced pluripotent stem cells (iPSCs), which can be differentiated into chondrocytes, are a promising source of cells for cartilage regenerative therapy. Currently, however, the methods for evaluating chondrogenic differentiation of iPSCs are very limited; the main techniques are based on the detection of chondrogenic genes and histological analysis of the extracellular matrix. The cell surface is coated with glycocalyx, a layer of glycoconjugates including glycosphingolipids (GSLs) and glycoproteins. The glycans in glycoconjugates play important roles in biological events, and their expression and structure vary widely depending on cell types and conditions. In this study, we performed a quantitative GSL-glycan analysis of human iPSCs, iPSC-derived mesenchymal stem cell like cells (iPS-MSC like cells), iPS-MSC-derived chondrocytes (iPS-MSC-CDs), bone marrow-derived mesenchymal stem cells (BMSCs), and BMSC-derived chondrocytes (BMSC-CDs) using glycoblotting technology. We found that GSL-glycan profiles differed among cell types, and that the GSL-glycome underwent a characteristic alteration during the process of chondrogenic differentiation. Furthermore, we analyzed the GSL-glycome of normal human cartilage and found that it was quite similar to that of iPS-MSC-CDs. This is the first study to evaluate GSL-glycan structures on human iPS-derived cartilaginous particles under micromass culture conditions and those of normal human cartilage. Our results indicate that GSL-glycome analysis is useful for evaluating target cell differentiation and can thus support safe regenerative medicine. Full article

(This article belongs to the Special Issue Structural and Functional Approach to the Glycan Diversity)

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17 pages, 3024 KiB

Open AccessArticle

Reconsideration of the Semaphorin-3A Binding Motif Found in Chondroitin Sulfate Using Galnac4s-6st-Knockout Mice

by Satomi Nadanaka, Shinji Miyata, Bai Yaqiang, Jun-ichi Tamura, Osami Habuchi and Hiroshi Kitagawa

Biomolecules 2020, 10(11), 1499; https://doi.org/10.3390/biom10111499 - 30 Oct 2020

Cited by 30 | Viewed by 3469

Abstract

The chondroitin sulfate (CS)-rich dense extracellular matrix surrounding neuron cell bodies and proximal dendrites in a mesh-like structure is called a perineuronal net (PNN). CS chains in PNNs control neuronal plasticity by binding to PNN effectors, semaphorin-3A (Sema3A) and orthodenticle homeobox 2. Sema3A recognizes CS-containing type-E disaccharide units (sulfated at O-4 and O-6 of N-acetylgalactosamine). Type-E disaccharide units are synthesized by N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S-6ST). In this study, we demonstrated that Sema3A accumulates in the PNNs surrounding parvalbumin cells, even in mice deficient in GalNAc4S-6ST. In addition, there were no differences in the number and structure of PNNs visualized by Cat316 antibody and Wisteria floribunda lectin, which recognize CS chains, between wild type and GalNAc4S-6ST knockout mice. Therefore, we re-examined the Sema3A binding motif found in CS chains using chemically synthesized CS tetrasaccharides. As a result, we found that non-sulfated GalNAc residues at the non-reducing termini of CS chains are required for the binding of Sema3A. Full article

(This article belongs to the Special Issue Structural and Functional Approach to the Glycan Diversity)

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19 pages, 6674 KiB

Open AccessFeature PaperArticle

Toolbox Accelerating Glycomics (TAG): Glycan Annotation from MALDI-TOF MS Spectra and Mapping Expression Variation to Biosynthetic Pathways

by Nobuaki Miura, Hisatoshi Hanamatsu, Ikuko Yokota, Kazue Okada, Jun-Ichi Furukawa and Yasuro Shinohara

Biomolecules 2020, 10(10), 1383; https://doi.org/10.3390/biom10101383 - 28 Sep 2020

Cited by 7 | Viewed by 2947

Abstract

Glycans present extraordinary structural diversity commensurate with their involvement in numerous fundamental cellular processes including growth, differentiation, and morphogenesis. Unlike linear DNA and protein sequences, glycans have heterogeneous structures that differ in composition, branching, linkage, and anomericity. These differences pose a challenge to developing useful software for glycomic analysis. To overcome this problem, we developed the novel Toolbox Accelerating Glycomics (TAG) program. TAG consists of three units: ‘TAG List’ creates a glycan list that is used for database searching in TAG Expression; ‘TAG Expression’ automatically annotates and quantifies glycan signals and draws graphs; and ‘TAG Pathway’ maps the obtained expression information to biosynthetic pathways. Herein, we discuss the concepts, outline the TAG process, and demonstrate its potential using glycomic expression profile data from Chinese hamster ovary (CHO) cells and mutants lacking a functional Npc1 gene (Npc1 knockout (KO) CHO cells). TAG not only drastically reduced the amount of time and labor needed for glycomic analysis but also detected and quantified more glycans than manual analysis. Although this study was limited to the analysis of N-glycans and free oligosaccharides, the glycomic platform will be expanded to facilitate the analysis of O-glycans and glycans of glycosphingolipids. Full article

(This article belongs to the Special Issue Structural and Functional Approach to the Glycan Diversity)

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Review

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22 pages, 5131 KiB

Open AccessEditor’s ChoiceReview

A Bittersweet Computational Journey among Glycosaminoglycans

by Giulia Paiardi, Maria Milanesi, Rebecca C. Wade, Pasqualina D’Ursi and Marco Rusnati

Biomolecules 2021, 11(5), 739; https://doi.org/10.3390/biom11050739 - 15 May 2021

Cited by 12 | Viewed by 4298

Abstract

Glycosaminoglycans (GAGs) are linear polysaccharides. In proteoglycans (PGs), they are attached to a core protein. GAGs and PGs can be found as free molecules, associated with the extracellular matrix or expressed on the cell membrane. They play a role in the regulation of a wide array of physiological and pathological processes by binding to different proteins, thus modulating their structure and function, and their concentration and availability in the microenvironment. Unfortunately, the enormous structural diversity of GAGs/PGs has hampered the development of dedicated analytical technologies and experimental models. Similarly, computational approaches (in particular, molecular modeling, docking and dynamics simulations) have not been fully exploited in glycobiology, despite their potential to demystify the complexity of GAGs/PGs at a structural and functional level. Here, we review the state-of-the art of computational approaches to studying GAGs/PGs with the aim of pointing out the “bitter” and “sweet” aspects of this field of research. Furthermore, we attempt to bridge the gap between bioinformatics and glycobiology, which have so far been kept apart by conceptual and technical differences. For this purpose, we provide computational scientists and glycobiologists with the fundamentals of these two fields of research, with the aim of creating opportunities for their combined exploitation, and thereby contributing to a substantial improvement in scientific knowledge. Full article

(This article belongs to the Special Issue Structural and Functional Approach to the Glycan Diversity)

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20 pages, 3185 KiB

Open AccessFeature PaperReview

Current Views on the Roles of O-Glycosylation in Controlling Notch-Ligand Interactions

by Wataru Saiki, Chenyu Ma, Tetsuya Okajima and Hideyuki Takeuchi

Biomolecules 2021, 11(2), 309; https://doi.org/10.3390/biom11020309 - 18 Feb 2021

Cited by 17 | Viewed by 4326

Abstract

The 100th anniversary of Notch discovery in Drosophila has recently passed. The Notch is evolutionarily conserved from Drosophila to humans. The discovery of human-specific Notch genes has led to a better understanding of Notch signaling in development and diseases and will continue to stimulate further research in the future. Notch receptors are responsible for cell-to-cell signaling. They are activated by cell-surface ligands located on adjacent cells. Notch activation plays an important role in determining the fate of cells, and dysregulation of Notch signaling results in numerous human diseases. Notch receptors are primarily activated by ligand binding. Many studies in various fields including genetics, developmental biology, biochemistry, and structural biology conducted over the past two decades have revealed that the activation of the Notch receptor is regulated by unique glycan modifications. Such modifications include O-fucose, O-glucose, and O-N-acetylglucosamine (GlcNAc) on epidermal growth factor-like (EGF) repeats located consecutively in the extracellular domain of Notch receptors. Being fine-tuned by glycans is an important property of Notch receptors. In this review article, we summarize the latest findings on the regulation of Notch activation by glycosylation and discuss future challenges. Full article

(This article belongs to the Special Issue Structural and Functional Approach to the Glycan Diversity)

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14 pages, 1277 KiB

Open AccessReview

The Role of APP O-Glycosylation in Alzheimer’s Disease

by Keiko Akasaka-Manya and Hiroshi Manya

Biomolecules 2020, 10(11), 1569; https://doi.org/10.3390/biom10111569 - 18 Nov 2020

Cited by 28 | Viewed by 4627

Abstract

The number of people with dementia is increasing rapidly due to the increase in the aging population. Alzheimer’s disease (AD) is a type of neurodegenerative dementia caused by the accumulation of abnormal proteins. Genetic mutations, smoking, and several other factors have been reported as causes of AD, but alterations in glycans have recently been demonstrated to play a role in AD. Amyloid-β (Aβ), a cleaved fragment of APP, is the source of senile plaque, a pathological feature of AD. APP has been reported to undergo N- and O-glycosylation, and several Polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts) have been shown to have catalytic activity for the transfer of GalNAc to APP. Since O-glycosylation in the proximity of a cleavage site in many proteins has been reported to be involved in protein processing, O-glycans may affect the cleavage of APP during the Aβ production process. In this report, we describe new findings on the O-glycosylation of APP and Aβ production. Full article

(This article belongs to the Special Issue Structural and Functional Approach to the Glycan Diversity)

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20 pages, 3216 KiB

Open AccessEditor’s ChoiceReview

Hyaluronan: Metabolism and Function

by Takashi Kobayashi, Theerawut Chanmee and Naoki Itano

Biomolecules 2020, 10(11), 1525; https://doi.org/10.3390/biom10111525 - 7 Nov 2020

Cited by 166 | Viewed by 14433

Abstract

As a major polysaccharide component of the extracellular matrix, hyaluronan plays essential roles in the organization of tissue architecture and the regulation of cellular functions, such as cell proliferation and migration, through interactions with cell-surface receptors and binding molecules. Metabolic pathways for biosynthesis and degradation tightly control the turnover rate, concentration, and molecular size of hyaluronan in tissues. Despite the relatively simple chemical composition of this polysaccharide, its wide range of molecular weights mediate diverse functions that depend on molecular size and tissue concentration. Genetic engineering and pharmacological approaches have demonstrated close associations between hyaluronan metabolism and functions in many physiological and pathological events, including morphogenesis, wound healing, and inflammation. Moreover, emerging evidence has suggested that the accumulation of hyaluronan extracellular matrix and fragments due to the altered expression of hyaluronan synthases and hyaluronidases potentiates cancer development and progression by remodeling the tumor microenvironment. In addition to the well-known functions exerted by extracellular hyaluronan, recent metabolomic approaches have also revealed that its synthesis can regulate cellular functions via the reprogramming of cellular metabolism. This review highlights the current advances in knowledge on the biosynthesis and catabolism of hyaluronan and describes the diverse functions associated with hyaluronan metabolism. Full article

(This article belongs to the Special Issue Structural and Functional Approach to the Glycan Diversity)

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22 pages, 11211 KiB

Open AccessReview

De Novo Structural Determination of the Oligosaccharide Structure of Hemocyanins from Molluscs

by Pavlina Dolashka, Asya Daskalova, Aleksandar Dolashki and Wolfgang Voelter

Biomolecules 2020, 10(11), 1470; https://doi.org/10.3390/biom10111470 - 22 Oct 2020

Cited by 8 | Viewed by 3123

Abstract

A number of studies have shown that glycosylation of proteins plays diverse functions in the lives of organisms, has crucial biological and physiological roles in pathogen–host interactions, and is involved in a large number of biological events in the immune system, and in virus and bacteria recognition. The large amount of scientific interest in glycoproteins of molluscan hemocyanins is due not only to their complex quaternary structures, but also to the great diversity of their oligosaccharide structures with a high carbohydrate content (2–9%). This great variety is due to their specific monosaccharide composition and different side chain composition. The determination of glycans and glycopeptides was performed with the most commonly used methods for the analysis of biomolecules, including peptides and proteins, including Matrix Assisted Laser Desorption/Ionisation–Time of Flight (MALDI-TOF-TOF), Liquid Chromatography - Electrospray Ionization-Mass Spectrometry (LC/ESI-MS), Liquid Chromatography (LC-Q-trap-MS/MS) or Nano- Electrospray Ionization-Mass Spectrometry (nano-ESI-MS) and others. The molluscan hemocyanins have complex carbohydrate structures with predominant N-linked glycans. Of interest are identified structures with methylated hexoses and xyloses arranged at different positions in the carbohydrate moieties of molluscan hemocyanins. Novel acidic glycan structures with specific glycosylation positions, e.g., hemocyanins that enable a deeper insight into the glycosylation process, were observed in Rapana venosa, Helix lucorum, and Haliotis tuberculata. Recent studies demonstrate that glycosylation plays a crucial physiological role in the immunostimulatory and therapeutic effect of glycoproteins. The remarkable diversity of hemocyanin glycan content is an important feature of their immune function and provides a new concept in the antibody–antigen interaction through clustered carbohydrate epitopes. Full article

(This article belongs to the Special Issue Structural and Functional Approach to the Glycan Diversity)

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