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Novel Chondroitin Sulfate Oligosaccharide Motifs as Biomarkers: Insights into Their Involvement in Brain Development

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Book cover Biochemical Roles of Eukaryotic Cell Surface Macromolecules

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 842))

Abstract

Chondroitin sulfate (CS) chains regulate the development of the central nervous system in vertebrates. They are the linear polysaccharide side chains of proteoglycans that consist of various sulfated repeating disaccharides, [–4GlcUAβ1–3GalNAcβ1–]n, in which GlcUA and GalNAc represent d-glucuronic acid and N-acetyl-d-galactosamine, respectively. CS chains containing disaccharide designated D-units, GlcUA(2-O-sulfate)–GalNAc(6-O-sulfate), play a role in brain development by interacting with the neurotrophic factor, pleiotrophin, which generates signaling. A series of octasaccharide sequences containing at least one D-unit, were previously isolated from embryonic pig brains using a pleiotrophin-immobilized affinity column. These similar yet distinct sugar sequences were termed “wobble oligosaccharide motifs” on account of their structural flexibility. Oligosaccharides containing D-units were recently isolated from shark fin cartilage to obtain more detailed structural information on the CS chains containing D-units that are involved in brain development. Seven novel hexasaccharide sequences, in addition to three previously reported sequences, were isolated after exhaustive digestion of the CS chains with the chondroitin lyase AC-I, which cannot act on galactosaminidic linkages adjacent to the D-units. Of the epitopes involved in cerebellar development in mammals, the novel epitope sequences ∆A-D-A, ∆A-D-D, and ∆A-B-D were identified in binding studies using an anti-CS monoclonal antibody, with the symbol ∆ referring to the 4,5-unsaturated bond of GlcUA residues generated by the lyase, while A, B, and C represented GlcUA-GalNAc(4-O-sulfate), GlcUA(2-O-sulfate)-GalNAc(4-O-sulfate), and GlcUA-GalNAc(6-O-sulfate), respectively. The significance of multiple CS oligosaccharide sequences in the brain and electrostatic potential distribution at their molecular surface during ligand binding have been discussed.

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Abbreviations

2AB:

2-Aminobenzamide

C4ST-1:

Chondroitin 4-O-sulfotransferase 1

C4ST-2:

Chondroitin 4-O-sulfotransferase 2

CS:

Chondroitin sulfate

D4ST-1:

Dermatan 4-O-sulfotransferase

DS:

Dermatan sulfate

GAG:

Glycosaminoglycan

GalNAc:

N-Acetyl-d-galactosamine

GalNAc4S-6ST:

GalNAc-4-sulfate 6-O-sulfotransferase

GlcUA:

d-Glucuronic acid

IdoUA:

l-Iduronic acid

mAb:

Monoclonal antibody

PG:

Proteoglycan

UST:

Uronyl 2-O-sulfotransferase

References

  • Atha DH, Lormeau JC, Petitou M, Rosenberg RD, Choay J (1987) Contribution of 3-O- and 6-O-sulfated glucosamine residues in the heparin-induced conformational change in antithrombin III. Biochemistry 26:6454–6461

    Article  CAS  Google Scholar 

  • Bao X, Nishimura S, Mikami T, Yamada S, Itoh N, Sugahara K (2004) Chondroitin sulfate/dermatan sulfate hybrid chains from embryonic pig brain, which contain a higher proportion of L-iduronic acid than those from the adult pig brain, exhibit neuritogenic and growth factor-binding activities. J Biol Chem 279(11):9765–9776

    Article  CAS  Google Scholar 

  • Bao X, Mikami T, Yamada S, Faissner F, Muramatsu T, Sugahara K (2005a) Heparin-binding growth factor, pleiotrophin, mediates neuritogenic activity of embryonic pig brain-derived chondroitin sulfate/dermatan sulfate hybrid chains. J Biol Chem 280(10):9180–9191

    Article  CAS  Google Scholar 

  • Bao X, Muramatsu T, Sugahara K (2005b) Demonstration of the pleiotrophin-binding oligosaccharide sequences isolated from chondroitin sulfate/dermatan sulfate hybrid chains of embryonic pig brains. J Biol Chem 280(42):35318–35328

    Article  CAS  Google Scholar 

  • Bishop JR, Schuksz M, Esko JD (2007) Heparan sulfate proteoglycans fine-tune mammalian physiology. Nature 446:1030–1037

    Article  CAS  Google Scholar 

  • Blanchard V, Chevalier F, Imberty A, Leeflang BR, Basappa, Sugahara K, Kamerling JP (2007) Conformational studies on five octasaccharides isolated from chondroitin sulfate using NMR spectroscopy and molecular modeling. Biochemistry 46(5):1167–1175

    Article  CAS  Google Scholar 

  • Casu B, Lindahl U (2001) Structure and biological interactions of heparin and heparan sulfate. Adv Carbohydr Chem Biochem 57:159–206

    Article  CAS  Google Scholar 

  • Clement AM, Nadanaka S, Masayama K, Mandl C, Sugahara K, Faissner A (1998) The DSD-1-epitope depends on sulfation, correlates with chondroitin sulfate D motifs, and is sufficient to promote neurite outgrowth. J Biol Chem 273(43):28444–28453

    Article  CAS  Google Scholar 

  • Clement A, Sugahara K, Faissner A (1999) Chondroitin sulfatae E promotes neurite outgrowth of embryonic day 18 hippocampal neurons. Neurosci Lett 269(3):125–128

    Article  CAS  Google Scholar 

  • Deepa SS, Kalayanamitra K, Ito Y, Kongtaweelert P, Fukui S, Yamada S, Mikami T, Sugahara K (2007) Novel sulfated octa- and decasaccharides from squid cartilage chondroitin sulfate-E: sequencing and application for determination of the epitope structure of monoclonal antibody MO-225. Biochemistry 46(9):2453–2465

    Article  CAS  Google Scholar 

  • Dick G, Tan CL, Alves JN, Ehlert EM, Miller GM, Hsieh-Wilson LC, Sugahara K, Oosterhof A, van Kuppevelt TH, Verhaagen J, Fawcett JW, Kwok JC (2013) Semaphorin 3A binds to the perineuronal nets via chondroitin sulfate type E motifs in rodent brains. J Biol Chem 288:27384–27395

    Article  CAS  Google Scholar 

  • Faissner A, Clement A, Lochter A, Streit A, Mandl C, Schachner M (1994) Isolation of a neural chondroitin sulfate proteoglycan with neurite outgrowth promoting properties. J Cell Biol 126(3):783–799

    Article  CAS  Google Scholar 

  • Ito Y, Hikino M, Yajima Y, Mikami T, Sirko L, von Holst A, Faissner A, Fukui S, Sugahara K (2005) Structural characterization of the epitopes of the monoclonal antibodies 473HD, CS-56, and MO-225 specific for chondroitin sulfate D-type using the oligosaccharide library. Glycobiology 15(6):593–603

    Article  CAS  Google Scholar 

  • Kitagawa H, Tsutsumi K, Tone Y, Sugahara K (1997) Developmental regulation of the sulfation profile of chondroitin sulfate chains in the chicken embryo brain. J Biol Chem 272(50):31377–31381

    Article  CAS  Google Scholar 

  • Kjellén L, Lindahl U (1991) Proteoglycans: structures and interactions. Annu Rev Biochem 60:443–475

    Article  Google Scholar 

  • Lindahl U (2014) A personal voyage through the proteoglycan field. Matrix Biol 35:3–7. doi:10.1016/j.matbio.2014.01.001

    Article  CAS  PubMed  Google Scholar 

  • Ly M, Leach FE 3rd, Laremore TN, Toida T, Amster IJ, Linhardt RJ (2011) The proteoglycan bikunin has a defined sequence. Nat Chem Biol 7(11):827–833

    Article  CAS  Google Scholar 

  • Maeda N, He J, Yajima Y, Mikami T, Sugahara K, Yabe T (2003) Heterogeneity of the chondroitin sulfate portion of phosphacan/6B4 proteoglycan regulates its binding affinity for pleiotrophin/HB-GAM. J Biol Chem 278(37):35805–35811

    Article  CAS  Google Scholar 

  • Mitsunaga C, Mikami T, Mizumoto S, Fukuda J, Sugahara K (2006) Chondroitin sulfate/dermatan sulfate hybrid chains in the development of cerebellum: spatiotemporal regulation of the expression of critical disulfated disaccharides by specific sulfotransferases. J Biol Chem 281(28):18942–18952

    Article  CAS  Google Scholar 

  • Miyata S, Komatsu Y, Yoshimura Y, Taya C, Kitagawa H (2012) Persistent cortical plasticity by upregulation of chondroitin 6-sulfation. Nat Neurosci 15(3):414–422

    Article  CAS  Google Scholar 

  • Mizumoto S, Murakoshi S, Kalayanamitra K, Deepa SS, Fukui S, Kongtawelert P, Yamada S, Sugahara K (2012) Highly sulfated hexasaccharide sequences isolated from chondroitin sulfate of shark fin cartilage: insights into the sugar sequences with bioctivities. Glycobiology 23(2):155–168

    Article  Google Scholar 

  • Nadanaka S, Clement A, Masayama K, Faissner A, Sugahara K (1988) Characteristic hexasaccharide sequences in octasaccharides derived from shark cartilage chondroitin sulfate D with a neurite outgrowth promoting activity. J Biol Chem 273(6):3296–3307

    Article  Google Scholar 

  • Perrimon N, Bernfield M (2001) Cellular functions of proteoglycans—an overview Semin. Semin Cell Dev Biol 12:65–67

    Article  CAS  Google Scholar 

  • Petitou M, van Boeckel CA (2004) A synthetic antithrombin III binding pentasaccharide is now a drug! What comes next? Angew Chem Int Ed Engl 43:3118–3133

    Article  CAS  Google Scholar 

  • Pothacharoen P, Ong-Chai S, Supaphun J, Kumja P, Wanaphirak C, Sugahara K, Hardingham T, Kongtawelert P (2006) Raised serum chondroitin sulfate epitope level in ovarian epithelial cancer. J Biochem 140(4):517–524

    Article  CAS  Google Scholar 

  • Pothacharoen P, Kalayanamitra K, Deepa SS, Fukui S, Hattori T, Fukushima N, Hardingham T, Kongtawelert P, Sugahara K (2007) Two related but distinct chondroitin sulfate mimetope octasaccharide sequences recognized by monoclonal antibody WF6. J Biol Chem 282(48):35232–35246

    Article  CAS  Google Scholar 

  • Purushothaman A, Fukuda J, Mizumoto S, ten Dam GB, van Kuppevelt TH, Kitagawa H, Mikami T, Sugahara K (2007) Functions of chondroitin sulfate/dermatan sulfate chains in the brain development: critical roles of E and iE disaccharide units recognized by a single chain antibody GD3G7. J Biol Chem 282(27):19442–19452

    Article  CAS  Google Scholar 

  • Purushothaman A, Sugahara K, Faissner A (2011) Chondroitin sulfate “wobble motifs” modulates the maintenance and differentiation of neural stem cells and their progeny. J Biol Chem 287(5):2935–2942

    Article  Google Scholar 

  • Shipp EL, Hsieh-Wilson LC (2007) Profiling the sulfation specificities of glycosaminoglycan interactions with growth factors and chemotactic proteins using microarrays. Chem Biol 14(2):195–208

    Article  CAS  Google Scholar 

  • Sugahara K, Mikami T (2007) Chondroitin/dermatan sulfate in the central nervous system. Curr Opin Struct Biol 17:536–545

    Article  CAS  Google Scholar 

  • Sugahara K, Mikami T, Uyama U, Mizuguchi S, Nomura K, Kitagawa H (2003) Recent advances in the structural biology of chondroitin sulfate and dermatan sulfate. Curr Opin Struct Biol 13:612–620

    Article  CAS  Google Scholar 

  • Takeuchi K, Yoshioka N, Higa Onaga S, Watanabe Y, Miyata S, Wada Y, Kudo C, Okada M, Ohko K, Oda K, Sato T, Yokoyama M, Matsushita N, Nakamura M, Okano H, Sakimura K, Kawano H, Kitagawa H, Igarashi M (2013) Chondroitin sulphate N-acetylgalactosaminyl-transferase-1 inhibits recovery from neural injury. Nat Commun 4:2740. doi:10.1038/ncomms3740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanaka M, Maeda N, Noda M, Marunouchi T (2003) A chondroitin sulfate proteoglycan PTPzeta /RPTPbeta regulates the morphogenesis of Purkinje cell dendrites in the developing cerebellum. J Neurosci 23(7):2804–2814

    Article  CAS  Google Scholar 

  • Thunberg L, Bäckström G, Lindahl U (1982) Further characterization of the antithrombin-binding sequence in heparin. Carbohydr Res 100:393–410

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by a Grant-in-Aid for Challenging Exploratory Research 25670018 and the Japan–Thailand Research Cooperative Program from the Japan Society for the Promotion of Science (JSPS), and a Grant in-Aid for Scientific Research on Innovative Areas 24110501 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT).

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Authors and Affiliations

  1. Faculty of Advanced Life Science Frontier Research Center for Post-Genomic Science and Technology 5F, North-21 West-11 Kita-ku, Sapporo, 001-0021, Japan

    Kazuyuki Sugahara Ph.D.

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  1. Kazuyuki Sugahara Ph.D.
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Correspondence to Kazuyuki Sugahara Ph.D. .

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Editors and Affiliations

  1. Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, Kolkata, India

    Abhijit Chakrabarti

  2. Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, India

    Avadhesha Surolia

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Sugahara, K. (2015). Novel Chondroitin Sulfate Oligosaccharide Motifs as Biomarkers: Insights into Their Involvement in Brain Development. In: Chakrabarti, A., Surolia, A. (eds) Biochemical Roles of Eukaryotic Cell Surface Macromolecules. Advances in Experimental Medicine and Biology, vol 842. Springer, Cham. https://doi.org/10.1007/978-3-319-11280-0_11

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