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Journal Article•DOI•

Major glycan structure underlying expression of the Lewis X epitope in the developing brain is O-mannose-linked glycans on phosphacan/RPTPβ.

Shohei Yaji1, Hiroshi Manya, Naoki Nakagawa1, Hiromu Takematsu1, Tamao Endo, Reiji Kannagi2, Toru Yoshihara3, Masahide Asano, Shogo Oka1 •
Kyoto University1, Aichi Medical University2, Kanazawa University3
01 Apr 2015-Glycobiology (Oxford University Press)-Vol. 25, Iss: 4, pp 376-385
TL;DR: The results revealed the importance of O-mannosylated glycan chains in the presentation of functional glycan epitopes in the brain.
Abstract: Glycosylation is a major protein modification. Although proteins are glycosylated/further modulated by several glycosyltransferases during trafficking from the endoplasmic reticulum to the Golgi apparatus, a certain glycan epitope has only been detected on a limited number of proteins. Of these glycan epitopes, Lewis X is highly expressed in the early stage of a developing brain and plays important roles in cell-cell interaction. The Lewis X epitope is comprised of a trisaccharide (Galβ1-4 (Fucα1-3) GlcNAc), and a key enzyme for the expression of this epitope is α1,3-fucosyltransferase 9. However, the scaffolding glycan structure responsible for the formation of the Lewis X epitope as well as its major carrier protein has not been fully characterized in the nervous system. Here we showed that the Lewis X epitope was mainly expressed on phosphacan/receptor protein tyrosine phosphatase β (RPTPβ) in the developing mouse brain. Expression of the Lewis X epitope was markedly reduced in β1,4-galactosyltransferase 2 (β4GalT2) gene-deficient mice, which indicated that β4GalT2 is a major galactosyltransferase required for the Lewis X epitope. We also showed that the Lewis X epitope almost disappeared due to the knockout of protein O-mannose β1,2-N-acetylglucosaminyltransferase 1, an N-acetylglucosaminyltransferase essential for the synthesis of O-mannosylated glycans, which indicated that the O-mannosylated glycan is responsible for presenting the Lewis X epitope. Since O-mannosylated glycans on phosphacan/RPTPβ could also present human natural killer-1, another glycan epitope specifically expressed in the nervous system, our results revealed the importance of O-mannosylated glycan chains in the presentation of functional glycan epitopes in the brain.

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Citations
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Journal Article•DOI•
Mammalian O-mannosyl glycans: Biochemistry and glycopathology.

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Tamao Endo
11 Jan 2019
TL;DR: The discovery of new glycan structures and the identification of highly regulated mechanisms of glycan processing will help researchers to understand glycan functions and develop therapeutic strategies.
Abstract: Glycosylation is an important posttranslational modification in mammals. The glycans of glycoproteins are classified into two groups, namely, N-glycans and O-glycans, according to their glycan-peptide linkage regions. Recently, O-mannosyl glycan, an O-glycan, has been shown to be important in muscle and brain development. A clear relationship between O-mannosyl glycans and the pathomechanisms of some congenital muscular dystrophies has been established in humans. Ribitol-5-phosphate is a newly identified glycan component in mammals, and its biosynthetic pathway has been elucidated. The discovery of new glycan structures and the identification of highly regulated mechanisms of glycan processing will help researchers to understand glycan functions and develop therapeutic strategies.

33 citations

Journal Article•DOI•
Mammalian brain glycoproteins exhibit diminished glycan complexity compared to other tissues

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Sarah E. Williams, Maxence Noel, Sylvain Lehoux, Murat Cetinbas, Ramnik J. Xavier, Ruslan I. Sadreyev, Edward M. Scolnick, Jordan W. Smoller, Richard D. Cummings, Robert G. Mealer 
12 Jan 2022-Nature Communications
TL;DR: In this paper , Asn-linked and Ser/Thr/Tyr-linked protein glycosylation between brain regions and sexes in mice was analyzed using several methodologies, and a consistent pattern was observed between regions and sex differences are minimal compared to those in plasma.
Abstract: Abstract Glycosylation is essential to brain development and function, but prior studies have often been limited to a single analytical technique and excluded region- and sex-specific analyses. Here, using several methodologies, we analyze Asn-linked and Ser/Thr/Tyr-linked protein glycosylation between brain regions and sexes in mice. Brain N-glycans are less complex in sequence and variety compared to other tissues, consisting predominantly of high-mannose and fucosylated/bisected structures. Most brain O-glycans are unbranched, sialylated O-GalNAc and O-mannose structures. A consistent pattern is observed between regions, and sex differences are minimal compared to those in plasma. Brain glycans correlate with RNA expression of their synthetic enzymes, and analysis of glycosylation genes in humans show a global downregulation in the brain compared to other tissues. We hypothesize that this restricted repertoire of protein glycans arises from their tight regulation in the brain. These results provide a roadmap for future studies of glycosylation in neurodevelopment and disease.

31 citations

Journal Article•DOI•
Neurons and Glia Modify Receptor Protein-tyrosine Phosphatase ζ (RPTPζ)/Phosphacan with Cell-specific O-Mannosyl Glycans in the Developing Brain

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Chrissa A. Dwyer1, Toshihiko Katoh2, Michael Tiemeyer2, Russell T. Matthews1•
State University of New York Upstate Medical University1, University of Georgia2
17 Apr 2015-Journal of Biological Chemistry
TL;DR: The results suggest that specific glycan modifications may tailor the function of this protein to the unique needs of specific cells, as well as identifying several novel O-mannose-linked glycan structures, including sulfo-N-acetyllactosamine containing modifications.

27 citations

Cites result from "Major glycan structure underlying e..."

  • ...Consistent with these observations, Oka and colleagues (52) have recently reported that RPTP /phosphacan is the primary carrier of the Lewis glycan in the developing brain....

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Journal Article•DOI•
Neural glycomics: the sweet side of nervous system functions

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Vladimir Sytnyk1, Iryna Leshchyns'ka1, Melitta Schachner2, Melitta Schachner3•
University of New South Wales1, Shantou University2, Rutgers University3
01 Jan 2021-Cellular and Molecular Life Sciences
TL;DR: This review describes the multiple studies on the functions of Lewis X, the human natural killer cell antigen-1 (HNK-1), as well as oligomannosidic and sialic (neuraminic) acids, and attempts to show the sophistication of these structures in ontogenetic development, synaptic function and plasticity, and recovery from trauma.
Abstract: The success of investigations on the structure and function of the genome (genomics) has been paralleled by an equally awesome progress in the analysis of protein structure and function (proteomics). We propose that the investigation of carbohydrate structures that go beyond a cell's metabolism is a rapidly developing frontier in our expanding knowledge on the structure and function of carbohydrates (glycomics). No other functional system appears to be suited as well as the nervous system to study the functions of glycans, which had been originally characterized outside the nervous system. In this review, we describe the multiple studies on the functions of LewisX, the human natural killer cell antigen-1 (HNK-1), as well as oligomannosidic and sialic (neuraminic) acids. We attempt to show the sophistication of these structures in ontogenetic development, synaptic function and plasticity, and recovery from trauma, with a view on neurodegeneration and possibilities to ameliorate deterioration. In view of clinical applications, we emphasize the need for glycomimetic small organic compounds which surpass the usefulness of natural glycans in that they are metabolically more stable, more parsimonious to synthesize or isolate, and more advantageous for therapy, since many of them pass the blood brain barrier and are drug-approved for treatments other than those in the nervous system, thus allowing a more ready access for application in neurological diseases. We describe the isolation of such mimetic compounds using not only Western NIH, but also traditional Chinese medical libraries. With this review, we hope to deepen the interests in this exciting field.

19 citations

Cites background from "Major glycan structure underlying e..."

  • ...The O-mannose-linked glycans on phosphacan/receptor protein tyrosine phosphatase β (RPTPβ) are the major glycan structures carrying the LewisX epitope in postnatal brains [17] (Fig....

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  • ...During postnatal mouse development, expression of the LewisX epitope increases after birth reaching the highest level at 14 days with high expression levels maintained also in adult brain [17]....

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  • ...O-mannosylated glycans play a key role in presenting the LewisX epitope: LewisX expression is reduced in mouse brains with ablated expression of O-linked-mannose β1,2-N-acetylglucosaminyl transferase 1 (POMGnT1), a N-acetylglucosaminyl transferase that is essential for the synthesis of O-mannosylated glycans [17]....

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Journal Article•DOI•
Selective 13 C‑Labels on Repeating Glycan Oligomers to Reveal Protein Binding Epitopes through NMR: Polylactosamine Binding to Galectins

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María Jesús Moure, Ana Gimeno, Sandra Delgado, Tammo Diercks, Geert-Jan Boons1, Geert-Jan Boons2, Jesús Jiménez-Barbero3, Jesús Jiménez-Barbero4, Ana Ardá3 •
Utrecht University1, University of Georgia2, Ikerbasque3, University of the Basque Country4
16 Aug 2021-Angewandte Chemie
TL;DR: A combined chemo-enzymatic synthesis/NMR-based methodology is presented to identify, in unambiguous manner, the distinctive binding epitope within repeating sugar oligomers when binding to protein receptors.
Abstract: A combined chemo-enzymatic synthesis/NMR-based methodology is presented to identify, in unambiguous manner, the distinctive binding epitope within repeating sugar oligomers when binding to protein receptors. The concept is based on the incorporation of 13 C-labels at specific monosaccharide units, selected within a repeating glycan oligomeric structure. No new chemical tags are added, and thus the chemical entity remains the same, while the presence of the 13 C-labeled monosaccharide breaks the NMR chemical shift degeneracy that occurs in the non-labeled compound and allows the unique identification of the different components of the oligomer. The approach is demonstrated by a proof-of-concept study dealing with the interaction of a polylactosamine hexasaccharide with five different galectins that display distinct preferences for these entities.

13 citations

References
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Journal Article•DOI•
SV40-transformed simian cells support the replication of early SV40 mutants.

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Yakov Gluzman1•
Cold Spring Harbor Laboratory1
01 Jan 1981-Cell
TL;DR: Three transformed lines of simian cells were established and found to contain T antigen; retain complete permissiveness for lytic growth of SV40; support the replication of tsA209 virus at 40 degrees C; and support the replicate of pure populations of SV 40 mutants with deletions in the early region.

2,445 citations

"Major glycan structure underlying e..." refers methods in this paper

  • ...COS-1 cells were purchased from American Type Culture Collection (ATCC CRL-1650) (Gluzman 1981)....

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Journal Article•DOI•
Glycosylation in Cellular Mechanisms of Health and Disease

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Kazuaki Ohtsubo1, Jamey D. Marth1•
University of California, San Diego1
08 Sep 2006-Cell
TL;DR: This review discusses the increasingly sophisticated molecular mechanisms being discovered by which mammalian glycosylation governs physiology and contributes to disease.

2,376 citations

"Major glycan structure underlying e..." refers background in this paper

  • ...Moreover, these "specific glycosylations" have been shown to determine the functionality of the carrier glycoproteins (Kleene and Schachner 2004; Ohtsubo and Marth 2006)....

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Journal Article•DOI•
On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database.

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Rolf Apweiler1, Henning Hermjakob1, Nathan Sharon2•
European Bioinformatics Institute1, Weizmann Institute of Science2
17 Dec 1999-Biochimica et Biophysica Acta
TL;DR: It is concluded that the majority of sequon containing proteins will be found to be glycosylated and that more than half of all proteins are glycoproteins.

1,756 citations

"Major glycan structure underlying e..." refers background in this paper

  • ...Glycosylation is one of the most frequent post-translational modifications of proteins (Apweiler et al. 1999)....

    [...]

Journal Article•DOI•
Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1.

[...]

Aruto Yoshida, Kazuhiro Kobayashi1, Hiroshi Manya, Kiyomi Taniguchi1, Hiroki Kano1, Mamoru Mizuno, Toshiyuki Inazu, Hideyo Mitsuhashi, Seiichiro Takahashi, Makoto Takeuchi, Ralf Herrmann, Volker Straub, Beril Talim2, Thomas Voit, Haluk Topaloglu2, Tatsushi Toda1, Tamao Endo •
Osaka University1, Boston Children's Hospital2
01 Nov 2001-Developmental Cell
TL;DR: It is suggested that interference in O-mannosyl glycosylation is a new pathomechanism for muscular dystrophy as well as neuronal migration disorder.

685 citations

"Major glycan structure underlying e..." refers background or methods in this paper

  • ...…known to be biosynthesized by the first enzyme POMT (Beltran-Valero de Bernabe et al. 2002), and N-acetylglucosamine at O ndokuz M ayis U niversity on N ovem ber 12, 2014 http://glycob.oxfordjournals.org/ D ow nloaded from (GlcNAc) could be transferred to O-mannose by POMGnT1 (Yoshida et al. 2001)....

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  • ...1997) and was synthesized by protein O-mannosyl transferase 1 (POMT1), POMT2, and protein O-mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) (Yoshida et al. 2001; Manya et al. 2004)....

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  • ...Mutations in the genes encoding POMT1/2 and POMGnT1 have been shown to cause muscular dystrophies with abnormal -DG glycosylation, designated as Walker-Warburg syndrome and muscle-eye-brain disease, respectively (Yoshida et al. 2001; Beltran-Valero de Bernabe et al. 2002; van Reeuwijk et al. 2005)....

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  • ...…(Siaα2-3Galβ1-4GlcNAcβ1-2Man) was discovered in bovine peripheral nerve α-dystroglycan (α-DG) (Chiba et al. 1997) and was synthesized by protein O-mannosyl transferase 1 (POMT1), POMT2, and protein O-mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) (Yoshida et al. 2001; Manya et al. 2004)....

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  • ...(GlcNAc) could be transferred to O-mannose by POMGnT1 (Yoshida et al. 2001)....

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Journal Article•DOI•
Mutations in the O-Mannosyltransferase Gene POMT1 Give Rise to the Severe Neuronal Migration Disorder Walker-Warburg Syndrome

[...]

Daniel Beltrán-Valero de Bernabé, Sophie Currier1, Alice Steinbrecher2, Jacopo Celli, Ellen van Beusekom, Bert van der Zwaag, Hülya Kayserili3, Luciano Merlini, David Chitayat4, William B. Dobyns5, Bru Cormand6, Ana Elina Lehesjoki7, Jesús Cruces, Thomas Voit, Christopher A. Walsh1, Hans van Bokhoven, Han G. Brunner •
Beth Israel Deaconess Medical Center1, Free University of Berlin2, Istanbul University3, University of Toronto4, University of Chicago5, University of Barcelona6, University of Helsinki7
01 Nov 2002-American Journal of Human Genetics
TL;DR: Immunohistochemical analysis of muscle from patients with POMT1 mutations corroborated the O-mannosylation defect, as judged by the absence of glycosylation of alpha-dystroglycan.
Abstract: Walker-Warburg syndrome (WWS) is an autosomal recessive developmental disorder characterized by congenital muscular dystrophy and complex brain and eye abnormalities. A similar combination of symptoms is presented by two other human diseases, muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Although the genes underlying FCMD (Fukutin) and MEB (POMGnT1) have been cloned, loci for WWS have remained elusive. The protein products of POMGnT1 and Fukutin have both been implicated in protein glycosylation. To unravel the genetic basis of WWS, we first performed a genomewide linkage analysis in 10 consanguineous families with WWS. The results indicated the existence of at least three WWS loci. Subsequently, we adopted a candidate-gene approach in combination with homozygosity mapping in 15 consanguineous families with WWS. Candidate genes were selected on the basis of the role of the FCMD and MEB genes. Since POMGnT1 encodes an O-mannoside N-acetylglucosaminyltransferase, we analyzed the possible implication of O-mannosyl glycan synthesis in WWS. Analysis of the locus for O-mannosyltransferase 1 (POMT1) revealed homozygosity in 5 of 15 families. Sequencing of the POMT1 gene revealed mutations in 6 of the 30 unrelated patients with WWS. Of the five mutations identified, two are nonsense mutations, two are frameshift mutations, and one is a missense mutation. Immunohistochemical analysis of muscle from patients with POMT1 mutations corroborated the O-mannosylation defect, as judged by the absence of glycosylation of α-dystroglycan. The implication of O-mannosylation in MEB and WWS suggests new lines of study in understanding the molecular basis of neuronal migration.

645 citations

"Major glycan structure underlying e..." refers background in this paper

  • ...Mutations in the genes encoding POMT1/2 and POMGnT1 have been shown to cause muscular dystrophies with abnormal -DG glycosylation, designated as Walker-Warburg syndrome and muscle-eye-brain disease, respectively (Yoshida et al. 2001; Beltran-Valero de Bernabe et al. 2002; van Reeuwijk et al. 2005)....

    [...]

  • ...O-mannosyl glycans are known to be biosynthesized by the first enzyme POMT (Beltran-Valero de Bernabe et al. 2002), and N-acetylglucosamine at O ndokuz M ayis U niversity on N ovem ber 12, 2014 http://glycob.oxfordjournals.org/ D ow nloaded from (GlcNAc) could be transferred to O-mannose by POMGnT1…...

    [...]

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