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Structural Basis for the Polysialylation of the Neural Cell Adhesion Molecule

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Book cover Structure and Function of the Neural Cell Adhesion Molecule NCAM

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 663))

Abstract

Polysialic acid is a unique glycan polymer composed of long chains of α2, 8-linked sialic acid residues; it is found on a small subset of mammalian proteins. The neural cell adhesion molecule, NCAM, is the most abundant polysialylated protein in mammalian cells. The presence of polysialic acid on NCAM has been demonstrated to decrease cell adhesion, and it is critical for a variety of processes including brain development, synaptic plasticity, axon guidance and pathfinding, neurite outgrowth, and general cell migration. Polysialic acid is also expressed on the surface of several highly metastatic cancers and has been implicated in cancer cell growth and invasiveness. This review will focus on the protein specificity of the polysialylation of NCAM by summarizing the current information on the sequence and structural requirements for NCAM recognition, and polysialylation by the polysialyltransferases, ST8Sia IV/PST and ST8Sia II/STX.

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References

  1. Johnson CP, Fujimoto I, Rutishauser U, Leckband DE (2005) Direct evidence that neural cell adhesion molecule (NCAM) polysialylation increases intermembrane repulsion and abrogates adhesion. J Biol Chem 280:137-145

    PubMed  CAS  Google Scholar 

  2. Rothbard JB, Brackenbury R, Cunningham BA, Edelman GM (1982) Differences in the carbohydrate structures of neural cell-adhesion molecules form adult and embryonic chicken brains. J Biol Chem 257:11064-11069

    PubMed  CAS  Google Scholar 

  3. Cunningham BA, Hemperly JJ, Murray BA, Prediger EA, Brackenbury R, Edelman GM (1987) Neural cell adhesion molecule: structure, immunoglobulin-like domains, cell surface modulation, and alternative RNA splicing. Science 236:799-806

    Article  PubMed  CAS  Google Scholar 

  4. Nelson RW, Bates PA, Rutishauser U (1995) Protein determinants for specific polysiaylation of the neural cell adhesion molecule. J Biol Chem 270:17171-17179

    Article  PubMed  CAS  Google Scholar 

  5. Acheson A, Sunshine JI, Rutishauser U (1991) NCAM polysialic acid can regulate both cell-cell and cell-substrate interactions. J Cell Biol 114:143-153

    Article  PubMed  CAS  Google Scholar 

  6. Landmesser L, Dahm L, Tang J, Rutishauser U (1990) Polysialic acid as a regulator of intramuscular nerve branching during embryonic development. Neuron 4:655-667

    Article  PubMed  CAS  Google Scholar 

  7. Rutishauser U, Landmesser L (1996) Polysialic acid in the vertebrate nervous system: a promoter of plasticity in cell-cell interactions. Trends Neurosci 19:422-427

    PubMed  CAS  Google Scholar 

  8. Durbec P, Cremer H (2001) Revisiting the function of PSA-NCAM in the nervous system. Mol Neurobiol 24:53-64

    Article  PubMed  CAS  Google Scholar 

  9. Kiss JZ, Troncoso E, Djebbara Z, Vutskits L, Muller D (2001) The role of neural cell adhesion molecules in plasticity and repair. Brain Res Rev 36:175-184

    Article  PubMed  CAS  Google Scholar 

  10. Bruses JL, Rutishauser U (2001) Roles, regulation, and mechanism of polysialic acid function during neural development. Biochimie 83:635-643

    Article  PubMed  CAS  Google Scholar 

  11. Hu H, Tomasiewicz H, Magnuson T, Rutishauser U (1996) The role of polysialic acid in migration of olfactory bulb interneuron precursors in the subventricular zone. Neuron 16:735-743

    Article  PubMed  CAS  Google Scholar 

  12. Cremer H, Chazal G, Lledo PM, Rougon G, Montaron MF, Mayo W, Le Moal M, Abrous DN (2000) PSA-NCAM: an important regulator of hippocampal plasticity. Int J Dev Neurosci 18:213-220

    Article  PubMed  CAS  Google Scholar 

  13. Shen H, Watanabe M, Tomasiewicz H, Rutishauser U, Magnuson T, Glass D (1997) Role of neural cell adhesion molecule and polysialic acid in mouse circadian clock function. J Neurosci 17:5221-5229

    PubMed  CAS  Google Scholar 

  14. Becker CG, Artola A, Gerardy-Schahn R, Becker T, Welzl H, Schachner M (1996) The polysialic acid modification of the neural cell adhesion molecule is involved in spatial learning and hippocampal long-term potentiation. J Neurosci Res 45:143-152

    Article  PubMed  CAS  Google Scholar 

  15. Muller D, Wang C, Skibo G, Toni N, Cremer H, Calaora V, Rougon G, Kiss JZ (1996) PSA-NCAM is required for activity-induced synaptic plasticity. Neuron 17:413-422

    Article  PubMed  CAS  Google Scholar 

  16. Rutishauser U (1996) Polysialic acid and the regulation of cell interactions. Curr Biol 8:679-684

    CAS  Google Scholar 

  17. El Maarouf A, Petridis AK, Rutishauser U (2006) Use of polysialic acid in repair of the central nervous system. Proc Natl Acad Sci USA 103:16989-16994

    Article  PubMed  CAS  Google Scholar 

  18. Michalides R, Kwa B, Springall D, van Zandwijk N, Koopman J, Hilkens J, Mooi W (1994) NCAM and lung cancer. Int. J. Cancer (Suppl.) 8:34-37

    Google Scholar 

  19. Hildebrandt H, Becker C, Gluer S, Rosner H, Gerardy-Schahn R, Rahmann H (1998) Polysialic acid on the neural cell adhesion molecule correlates with expression of polysialyltransferases and promotes neuroblastoma cell growth. Cancer Res 58:779-784

    PubMed  CAS  Google Scholar 

  20. Tanaka F, Otake Y, Nakagawa T, Kawano Y, Miyahara R, Li M, Yanagihara K, Nakayama J, Fujimoto I, Ikenaka K, Wada H (2000) Expression of polysialic acid and STX, a human polysialyltransferase, is correlated with tumor progression in non-small cell lung cancer. Cancer Res 60:3072-3080

    PubMed  CAS  Google Scholar 

  21. Gluer S, Schelp C, Gerardy-Schahn R, von Schweinitz D (1998) Polysialylated neural cell adhesion molecule as a marker for differential diagnosis in pediatric tumors. J Pediatr Surg 33:1516-1520

    Article  PubMed  CAS  Google Scholar 

  22. Komminoth P, Roth J, Lackie PM, Bitter-Suermann D, Heitz PU (1991) Polysialic acid of the neural cell adhesion molecule distinguishes small cell lung carcinoma from carcinoids. Am J Pathol 139:297-304

    PubMed  CAS  Google Scholar 

  23. Livingston BD, Jacobs JL, Glick MC, Troy FA (1988) Extended polysialic acid chains (n>55) in glycoproteins from human neuroblastoma cells. J Biol Chem 263:9443-9448

    PubMed  CAS  Google Scholar 

  24. Roth J, Zuber C, Wagner P, Taatjes DJ, Weiserber C, Heitz PU, Gordis C, Bitter-Suermann D (1988) Reexpression of polysialic acid units on the neural cell adhesion molecule in Wilms’ tumor. Proc Natl Acad Sci USA 85:2999-3003

    Article  PubMed  CAS  Google Scholar 

  25. Suzuki M, Nakayama J, Suzuki A, Angata K, Chen S, Sakai K, Hagihara K, Yamaguchi Y, Fukuda M (2005) Polysialic acid facilitates tumor invasion by glioma cells. Glycobiology 15:887-894

    Article  PubMed  CAS  Google Scholar 

  26. Cremer H, Lange R, Christoph A, Plomann M, Vopper G, Roes J, Brown R, Baldwin S, Kraemer P, Scheff S, Barthels D, Rajewsky K, Wille W (1994) Inactivation of the N-CAM gene in mice results in size reduction of the olfactory bulb and deficits in spatial learning. Nature 367:455-459

    Article  PubMed  CAS  Google Scholar 

  27. Angata K, Long JM, Bukalo O, Lee W, Dityatev A, Wynshaw-Boris A, Schachner M, Fukuda M, Marth JD (2004) Sialyltransferase ST8Sia-II assembles a subset of polysialic acid that directs hippocampal axonal targeting and promotes fear behavior. J Biol Chem 279:32603-32613

    Article  PubMed  CAS  Google Scholar 

  28. Eckhardt M, Bukalo O, Chazal G, Wang L, Goridis C, Schachner M, Gerardy-Schahn R, Cremer H, Dityatev A (2000) Mice deficient in the polysialyltransferase ST8SiaIV/PST-1 allow discrimination of the roles of neural cell adhesion molecule protein and polysialic acid in neural development and synaptic plasticity. J Neurosci 20:5234-5244

    PubMed  CAS  Google Scholar 

  29. Weinhold B, Hildebrandt H, Seindenfaden R, Muhlenhoff M, Oschlies M, Gerardy-Schahn R (2004) Loss of polysialic acid results in serious neurological defects in mice. Glycobiology 14:1141

    Google Scholar 

  30. Weinhold B, Seidenfaden R, Rockle I, Muhlenhoff M, Schertzinger F, Conzelmann S, Marth JD, Gerardy-Schahn R, Hildebrandt H (2005) Genetic ablation of polysialic acid causes severe neurodevelopmental defects rescued by deletion of the neural cell adhesion molecule. J Biol Chem 280:42971-42977

    Article  PubMed  CAS  Google Scholar 

  31. Angata K, Fukuda M (2003) Polysialyltransferases: major players in polysialic acid synthesis on the neural cell adhesion molecule. Biochimie 85:195-206

    Article  PubMed  CAS  Google Scholar 

  32. Finne J, Finne U, Deagostini-Bazin H, Gordis C (1983) Occurence of α2-8 linked polysialosyl units in neural cell adhesion molecule. Biochem Biophys Res Commun 112:482-487

    Article  PubMed  CAS  Google Scholar 

  33. James WM, Agnew WS (1987) Multiple oligosaccharide chains in the voltage-dependent NA channel from electrophorus electricus: Evidence for α-2, 8-linked polysialic acid. Biochem Biophys Res Commun 148:817-826

    Article  PubMed  CAS  Google Scholar 

  34. Zuber C, Lackie P, Catterall W, Roth J (1992) Polysialic acid is associated with sodium channels and the neural cell adhesion molecule N-CAM in adult rat brain. J Biol Chem 267:9965-9971

    PubMed  CAS  Google Scholar 

  35. Close BE, Colley KJ (1998) In vivo autopolysialylation and localization of the polysialyltransferases PST and STX. J Biol Chem 273:34586-34593

    Article  PubMed  CAS  Google Scholar 

  36. Yabe U, Sato C, Matsuda T, Kitajima K (2003) Polysialic acid in human milk: CD36 is a new member of mammalian polysialic acid-containing glycoprotein. J Biol Chem 278:13875-13880

    Article  PubMed  CAS  Google Scholar 

  37. Curreli S, Arany Z, Gerardy-Schahn R, Mann D, Stamatos NM (2007) Polysialylated neuropilin-2 is expressed on the surface of human dendritic cells and modulates dendritic cell-T lymphocyte interactions. J Biol Chem 282:30346-30356

    Article  PubMed  CAS  Google Scholar 

  38. Paulson JC, Colley KJ (1989) Glycosyltransferases: Structure, localization, and control of cell type-specific glycosylation. J Biol Chem 264:17615-17618

    PubMed  CAS  Google Scholar 

  39. Baenziger JU (1994) Protein-specific glycosyltransferases: how and why they do it! FASEB J 8:1019-1025

    PubMed  CAS  Google Scholar 

  40. Baranski TJ, Faust P, Kornfeld S (1990) Generation of a lysosomal enzyme targeting signal in the secretory protein pepsinogen. Cell 63:281-291

    Article  PubMed  CAS  Google Scholar 

  41. Manzella SM, Hooper LV, Baenziger JU (1996) Oligosaccharides containing β1, 4-linked N-acetylgalactosamine, a paradigm for protein-specific glycosylation. J. Biol. Chem. 271:12117-12120

    Article  PubMed  CAS  Google Scholar 

  42. Sousa M, Parodi AJ (1995) The molecular basis for the recognition of misfolded glycoproteins by the UDP-Glc:glycoprotein glucosyltransferase. EMBO J 14:4196-4203

    PubMed  CAS  Google Scholar 

  43. Trombetta ES, Helenius A (2000) Conformational requirements for glycoprotein reglucosylation in the endoplasmic reticulum. J Cell Biol 148:1123-1129

    Article  PubMed  CAS  Google Scholar 

  44. Rampal R, Li ASY, Moloney MJ, Georgiou SA, Luther KB, Nita-Lazar A, Haltiwanger R (2005) Lunatic fringe, Manic fringe, and Radical fringe recognize similar specificity determinants in O-fucosylated EGF repeats. J Biol Chem 280:42454-42463

    Article  PubMed  CAS  Google Scholar 

  45. Shao L, Moloney DJ, Haltiwanger R (2003) Fringe modifies O-fucose on mouse Notch1 at epidermal growth factor-like repeats within the ligand-binding site and the Abruptex region. J Biol Chem 278:7775-7782

    Article  PubMed  CAS  Google Scholar 

  46. Mengeling BJ, Manzella SM, Baenziger JU (1995) A cluster of basic amino acids within an α-helix is essential for α-subunit recognition by the glycoprotein hormone N-acetylgalactosaminyltransferase. Proc Natl Acad Sci USA 92:502-506

    Article  PubMed  CAS  Google Scholar 

  47. Smith PL, Baenziger JU (1992) Molecular basis of recognition by the glycoprotein hormone-specific N-acetlygalactosmine-transferase. Proc Natl Acad Sci USA 89:329-333

    Article  PubMed  CAS  Google Scholar 

  48. Dahms NM, Lobel P, Kornfeld S (1989) Mannose 6-phosphate receptors and lysosomal enzyme targeting. J Biol Chem 254:12115-12118

    Google Scholar 

  49. Kornfeld S (1986) Trafficking of lysosomal enzymes in normal and disease states. J Clin Invest 77:1-6

    Article  PubMed  CAS  Google Scholar 

  50. Baranski TJ, Cantor AB, Kornfeld S (1992) Lysosomal enzyme phosphorylation. I. Protein recognition determinants in both lobes of procathepsin D mediate its interaction with UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. J Biol Chem 267:23342-23348

    PubMed  CAS  Google Scholar 

  51. Baranski TJ, Koelsch G, Hartsuck JA, Kornfeld S (1991) Mapping and molecular modeling of a recognition domain for lysosomal enzyme targeting. J Biol Chem 266:23365-23372

    PubMed  CAS  Google Scholar 

  52. Cantor AB, Baranski TJ, Kornfeld S (1992) Lysosomal enzyme phosphorylation. II. Protein recognition determinants in either lobe of procathepsin D are sufficient for phosphorylation of both the amino and carboxyl lobe oligosaccharides. J Biol Chem 267:23349-23356

    PubMed  CAS  Google Scholar 

  53. Steet R, Lee WS, Kornfeld S (2005) Identification of the minimal lysosomal enzyme recognition domain in cathepsin D. J Biol Chem 280:33318-33323

    Article  PubMed  CAS  Google Scholar 

  54. Kojima N, Tachida Y, Yoshida Y, Tsuji S (1996) Characterization of mouse ST8Sia II (STX) as a neural cell adhesion molecule-specific polysialic acid synthase: Requirement of core α1, 6-linked fucose and a polypeptide chain for polysialylation. J Biol Chem 271:19457-19463

    Article  PubMed  CAS  Google Scholar 

  55. Angata K, Suzuki M, McAuliffe J, Ding Y, Hindsgaul O, Fukuda M (2000) Differential biosynthesis of polysialic acid on neural cell adhesion molecule (NCAM) and oligosaccharide acceptors by three distinct α2, 8-sialyltransferases, ST8Sia IV (PST), ST8Sia II (STX), and ST8Sia III. J Biol Chem 275:18594-18601

    Article  PubMed  CAS  Google Scholar 

  56. Close BE, Tao K, Colley KJ (2000) Polysialyltransferase-1 autopolysialylation is not requisite for polysialylation of neural cell adhesion molecule. J Biol Chem 275:4484-4491

    Article  PubMed  CAS  Google Scholar 

  57. Close BE, Wilkinson JM, Bohrer TJ, Goodwin CP, Broom LJ, Colley KJ (2001) The polysialyltransferase ST8Sia II/STX: posttranslational processing and role of autopolysialylation in the polysialylation of neural cell adhesion molecule. Glycobiology 11:997-1008

    Article  PubMed  CAS  Google Scholar 

  58. Close BE, Mendiratta SS, Geiger KM, Broom LJ, Ho LL, Colley KJ (2003) The minimal structural domains required for neural cell adhesion molecule polysialylation by PST/ST8Sia IV and STX/ST8Sia II. J Biol Chem 278:30796-30805

    Article  PubMed  CAS  Google Scholar 

  59. Fujimoto I, Bruses JL, Rutishauser U (2001) Regulation of cell adhesion by polysialic acid. Effects on cadherin, immunoglobulin cell adhesion molecule, and integrin function and independence from neural cell adhesion molecule binding or signaling activity. J Biol Chem 276:31745-31751

    Article  PubMed  CAS  Google Scholar 

  60. Peterson TE, Thogersen HC, Skorstengaard K, Vibe-Pedersen K, Sahl P, Sottrup-Jensen L, Magnusson S (1983) Partial primary structure of bovine plasma fibronectin: three types of internal homology. Proc Natl Acad Sci USA 80:137-141

    Article  Google Scholar 

  61. Bork P, Doolittle RF (1992) Proposed acquisition of an animal protein domain by bacteria. Proc Natl Acad Sci USA 89:8990-8994

    Article  PubMed  CAS  Google Scholar 

  62. Bateman A, Birney E, Cerruti L, Durbin R, Etwiller L, Eddy SR, Griffiths-Jones S, Howe KL, Marshall M, Sonnhammer EL (2002) The Pfam protein families database. Nuc Acids Res 30:276-280

    Article  CAS  Google Scholar 

  63. Williams AF, Barclay AN (1988) The immunoglobulin superfamily-domains for cell surface recognition. Annu Rev Immunol 6:381-405

    Article  PubMed  CAS  Google Scholar 

  64. Mendiratta SS, Sekulic N, Lavie A, Colley KJ (2005) Specific amino acids in the first fibronectin type III repeat of the neural cell adhesion molecule play a role in its recognition and polysialylation by the polysialyltransferase ST8Sia IV/PST. J Biol Chem 280:32340-32348

    Article  PubMed  CAS  Google Scholar 

  65. Mendiratta SS, Sekulic N, Hernandez-Guzman FG, Close BE, Lavie A, Colley KJ (2006) A novel α-helix in the first fibronectin type III repeat of the neural cell adhesion molecule is critical for N-glycan polysialylation. J Biol Chem 281:36052-36059

    Article  PubMed  CAS  Google Scholar 

  66. Walsh FS, Parekh RB, Moore SE, Dickson G, Barton CH, Gower HJ, Dwek RA, Rademacher TW (1989) Tissue specific O-linked glycosylation of the neural cell adhesion molecule (N-CAM). Development 105:803-811

    PubMed  CAS  Google Scholar 

  67. Suzuki M, Angata K, Fukuda M (2000) Polysialic acid attached to O-linked oligosaccharides in NCAM: biosynthesis and function Glycobiology 10:1113 (Abstract)

    Google Scholar 

  68. Martersteck CM, Kedersha NL, Drapp DA, Tsui TG, Colley KJ (1996) Unique α2, 8-polysialylated glycoproteins in breast cancer and leukemia cells. Glycobiology 6:289-302

    Article  PubMed  CAS  Google Scholar 

  69. Becker JW, Erickson HP, Hoffman S, Cunningham BA, Edelman GM (1989) Topology of cell adhesion molecules. Proc Natl Acad Sci USA 86:1088-1092

    Article  PubMed  CAS  Google Scholar 

  70. Hall AK, Rutishauser U (1987) Visualization of neural cell adhesion molecule by electron microscopy. J Cell Biol 104:1579-1586

    Article  PubMed  CAS  Google Scholar 

  71. Alenius M, Bohm S (2003) Differential function of RNCAM isoforms in precise target selection of olfactory sensory neurons. Development 130:917-927

    Article  PubMed  CAS  Google Scholar 

  72. Walz A, Mombaerts P, Greer CA, Treloar HB (2006) Disrupted compartmental organization of axons and dendrites within olfactory glomeruli of mice deficient in the olfactory cell adhesion molecule. OCAM Mol Cell Neurosci 32:1-14

    Article  CAS  Google Scholar 

  73. Yoshihara Y, Kawasaki M, Tamada A, Fujita H, Hayashi H, Kagamiyama H, Mori K (1997) OCAM: A new member of the neural cell adhesion molecule family related to zone-to-zone projection of olfactory and vomeronasal axons. J Neurosci 17:5830-5842

    PubMed  CAS  Google Scholar 

  74. Galuska SP, Geyer R, Gerardy-Schahn R, Muhlenhoff M, Geyer H (2007) Enzyme-dependent variations in the polysialylation of the neural cell adhesion molecule NCAM in vivo. J Biol Chem 283:1463-1471

    Article  PubMed  Google Scholar 

  75. Galuska SP, Oltmann-Norden I, Geyer H, Weinhold B, Kuchelmeister K, Hildebrandt H, Gerardy-Schahn R, Geyer R, Muhlenhoff M (2006) Polysialic acid profiles of mice expressing variant allelic combinations of the polysialyltransferases ST8SiaII and ST8SiaIV. J Biol Chem 281:31605-31615

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

I would like to thank Deirdre Foley for providing Figure 5. I am also very grateful to Dr. Nikolina Sekulic and Saugata Hazra for providing the structural representations in Figures 2 and 3. I would also like to extend my thanks to members of my laboratory (K. Swartzentruber, D. Foley, W. Zhao, and M. Thompson) for critiquing this manuscript and helping with its assembly. This work was supported by NIH RO1 GM63843 to K. J. C.

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  1. Department of Biochemistry and Molecular Genetics, University of Illinois, College of Medicine, Chicago, IL, USA

    Karen J. Colley

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Correspondence to Karen J. Colley .

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  1. Panum Institute, Dept. Regenerative Medicine, University of Copenhagen, Blegdamsvej 3C, Koebenhavn N, 2200, Denmark

    Vladimir Berezin

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Colley, K.J. (2010). Structural Basis for the Polysialylation of the Neural Cell Adhesion Molecule. In: Berezin, V. (eds) Structure and Function of the Neural Cell Adhesion Molecule NCAM. Advances in Experimental Medicine and Biology, vol 663. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1170-4_7

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