Search:
Computing and Library Services - delivering an inspiring information environment

An NMR and molecular modelling study on the solution conformation of Heparan Sulphate: new insights into the relationship between structure and function

Murphy, K.J. (2007) An NMR and molecular modelling study on the solution conformation of Heparan Sulphate: new insights into the relationship between structure and function. Doctoral thesis, University of Huddersfield.

[img]
Preview
PDF
Download (26MB) | Preview

Abstract

A deeper insight into the structural biology of HS is key to understanding its nearuniversal
functional role as a co-receptor for growth factors and morphogens. Due to the
extreme difficulty in preparing homogeneous HS oligosaccharides for structural and
functional studies, traditionally, oligosaccharides derived from the related molecule
heparin are used as HS structural models. In this study a number of authentic HS derived
hexasaccharides, in addition to heparin derived hexasaccharides, have been purified in
sufficient quantity to permit a detailed NMR and molecular modelling based analysis of
their three dimensional structure. The primary sequence of one HS derived
oligosaccharide has never previously been published. Studies on all oligosaccharides and
their chemically de-2-O-sulphated derivatives have revealed additional new insights into
the structural influence of sulphate groups. Consistent with previous studies, at the
monosaccharide level, sulphation was found to influence iduronate conformational
behaviour. However, with the data presented, a number of gaps in the literature have now
been filled, and it is now possible for the first time to predict the balance of iduronate
conformational equilibria within any HS monosaccharide sequence. Sulphation was also
found to influence the overall topology of the oligosaccharide chains themselves. In
particular, for the first time NMR data is presented to show that local deviations may
occur along the helical axis of each oligosaccharide when it is free in solution.
Polyacrylamide gel electrophoresis data and molecular dynamic modelling data are
presented to suggest that the rate at which local deviations occur may be influenced by
the sulphation pattern contained within a particular oligosaccharide. The functional
implications of these and other new structural insights are discussed, and in particular are
related to a library of HS derived decasaccharide structures previously tested for
biological activity

▼ Jump to Download Statistics
Item Type: Thesis (Doctoral)
Additional Information: Copyright: The Author 2007
Subjects: Q Science > QD Chemistry
Schools: School of Applied Sciences
References: Abeijon, C., Mandon, E. C. and Hirschberg, C. B. (1997). Transporters of nucleotide sugars, nucleotide sulfate and ATP in the Golgi apparatus. Trends. Biochem. Sci. 22(6): 203-7. Ai, X., Do, A., Kusche-Gullberg, M., Lindahl, U., Lu, K. and Emerson, J. C. P. (2006). Substrate specificity and domain functions of extracelluar Heparan Sulfate 6-Oendosulfatases, QSulf1 and QSulf2. J. Biol. Chem 281(8): 4969-4976. Ai, X., Do, A., Lozynska, O., Kusche_Gullberg, M., Lindahl, U. and P., E. J. C. (2003). QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling. J. Cell. Biol 162(2): 341-351. Aikawa, J. and Esko, J. D. (1999). Molecular cloning and expression of a third member of the heparan sulfate/heparin GlcNAc N-deacetylase/ N-sulfotransferase family. J. Biol. Chem. 274(5): 2690-5. Aikawa, J., Grobe, K., Tsujimoto, M. and Esko, J. D. (2001). Multiple isozymes of heparan sulfate/heparin GlcNAc N-deacetylase/GlcN N-sulfotransferase. Structure and activity of the fourth member, NDST4. J. Biol. Chem. 276(8): 5876-82. Andres, J. L., DeFalcis, D., Noda, M. and Massaque, J. (1992). Binding of two growth factor families to seperate domains of the proteoglycan betaglycan. J. Biol. Chem. 267: 5927-5930. Angulo, J., Hricovini, M., Gairi, M., Guerrini, M., de Paz, J. L., Ojeda, R., Martin- Lomas, M. and Nieto, P. M. (2005). Dynamic properties of biologically active synthetic heparin-like hexasaccharides. Glycobiology 15(10): 1008-15. Angulo, J., Nieto, P. M. and Martin-Lomas, M. (2003). A molecular dynamics description of the conformational flexibility of the L-iduronate ring in glycosaminoglycans. Chem. Commun: 1512-1513. Ashikari-Hada, S., Habuchi, H., Kariya, Y., Itoh, N., Reddi, A. H. and Kimata, K. (2004). Characterization of growth factor-binding structures in heparin/heparan sulfate using an octasaccharide library. J Biol Chem 279(13): 12346-54. Asundi, V. K. and Carey, D., J. (1995). Self association of N-syndecan (syndecan-3) core protein is mediated by a novel structural motif in the transmembrane domain and ectodomain flanking regions. J. Biol. Chem. 270(26404-26410). Baciu, P. C. and Goetinck, P. F. (1995). Protein Kinase C regulates recruitment of syndecan-4 into focal adhesions. Mol. Biol. Cell. 6: 1503-1513. Baciu, P. C., Saonoella, S., Lee, S. H., Denhez, F., Leuthardt, D. and Goetinck, P. F. (2000). Syndesmos, a protein that interacts with the cytoplasmic domain of syndecan-4, mediates cell spreading and actin cytoskeletal organisation. J. Cell. Sci. 113(2): 315-324. Bazin, H. G., Capila, I. and Linhardt, R. J. (1998). Conformational study of synthetic 4- uronate monosaccharides and glycosaminoglycan derived disaccharides. Carbohydr. Res. 309: 135-144. Becker, C. F., Guimaraes, J. A. and Verli, H. (2005). Molecular dynamics and atomic charge calculations in the study of heparin conformation in aqueous solution. Carbohydr. Res. 340: 1499-1507. Becker, E. D. (2000). High Resolution NMR: Theory and Chemical Applications. San Diego, Academic Press. 357 Bellin, R., Capila, I., Lincecum, J., Park, P. W., Reizes, O. and Bernfield, M. R. (2003). Unlocking the secrets of syndecans: Transgenic organisms as a potential key. Glycoconj. J. 19: 295-304. Bernfield, M., Kokenyesi, R., Kato, M., Hinkes, M. T., Spring, J., Gallo, R. L. and Lose, E. J. (1992). Biology of the syndecans: a family of transmembrane heparan sulfate proteoglycans. Annu. Rev. Cell. Biol. 8: 365-93. Bjork, I. and Lindahl, U. (1982). Mechanism of the anticoagulant action of heparin. Mol. Cell. Biochem. 48(3): 161-82. Blackhall, F. H., Merry, C. L., Lyon, M., Jayson, G. C., Folkman, J., Javaherian, K. and Gallagher, J. T. (2003). Binding of endostatin to endothelial heparan sulphate shows a differential requirement for specific sulphates. Biochem. J. 375: 131-139. Bourdon, M. A., Oldberg, A., Pierschbacher, M. and Ruoslahti, E. (1985). Molecular cloning and sequence analysis of a chondroitin sulfate proteoglycan cDNA. Proc. Natl. Acad. Sci. USA. 82(5): 1321-5. Brown, J. C., Sasaki, T., Gohring, W., Yamada, Y. and Timpl, R. (1997). The C-terminal domain V of perlecan promotes beta-1 integrin- mediated cell adhesion, binds heparin, nidogen and fibulin-2 and can be modified by glycosaminoglycans. Eur. J. Biochem. 250: 39-46. Bubb, W. A. (2003). NMR spectroscopy in the study of carbohydrates: characterizing the structural complexity. Concepts. Magn. Reson. 19A(1): 1-19. Bull, R. J., Robinson, M., Laurie, R. D., Stoner, E., Greisiger, J. R., Meier, J. R. and Strober, J. (1984). Carcinogenic effect of acrylamide in Sencar and A/J mice. Cancer. Res. 44: 107-111. Cardin, A. D. and Weintraub, H. J. R. (1989). Molecular modelling of proteinglycosaminoglycan interactions. Arteriosclerosis 9: 21-32. Carey, D., J., Conner, K., Asundi, V. K., O'Mahony, D. J., Stahl, R. C., Showalter, L. J., Cizmeci-Smith, G., Hartman, J. and Rothblum, L. I. (1997). cDNA cloning genomic organisation and in vivo expression of rat N-syndecan. J. Biol. Chem. 272. Carey, D. J. (1997). Syndecans: multifunctional cell-surface co-receptors. Biochem. J. 327: 1-16. Carey, F. A. (1992). Organic Chemistry, McGraw-Hill, Inc. Case, D. A., Cheatham, T. E. I., Darden, T., Gohlke, H., Luo, R., Merz, K. M. M. J., Onufriev, A., Simmerling, C., Wang, B. and Woods, R. J. (2005). The Amber biomolecular simulation programs. J. Comput. Chem. 26: 1668-1688. Case, D. A., Darden, T. E., Cheatham III, T. E., Simmerling, C. L., Wang, J., Duke, R. E., Luo, R., Merz, K. M., Wang, B., Pearlman, D. A., et al. (2004). AMBER 8. University of California, San Francisco. Cheung, W. F., Eriksson, I., Kusche_Gullberg, M., Lindhal, U. and Kjellen, L. (1996). Expression of the mouse mastocytoma glucosaminyl N-deacetylase/ Nsulfotransferase in human kidney 293 cells results in increased N-sulfation of heparan sulfate. Biochemistry. 35(16): 5250-6. Chuang, W. L., Christ, M. D., Peng, J. and Rabenstein, D. L. (2000). An NMR and molecular modelling study of the site-specific binding of Histamine by Heparin, 358 chemically modified Heparin and Heparin-derived oligosaccharides. Biochemistry 39: 3542-3555. Chuang, W. L., Christ, M. D. and Rabenstein, D. L. (2001). Determination of the primary structures of heparin and heparan sufate derived oligosacchrides using band selective homonuclear decoupled two dimensional 1H NMR experiments. Anal. Chem. 73: 2310-2316. Chuang, W. L., McAllister, H. and Rabenstein, D. L. (2002). Hexasaccharides from the histamine-modified depolymerization of porcine intestinal mucosal heparin. Carbohydr. Res. 337(10): 935-45. Cifonelli, J. A. and King, J. A. (1977). Structural characteristics of heparan sulfates with varying sulfate contents. Biochemistry. 16(10): 2137-41. Clamp, A., Blackhall, F. H., Henrioud, A., Jayson, G. C., Javaherian, K., Esko, J., Gallagher, J. T. and Merry, C. L. R. (2006). The morphogenic properties of oligomeric endostatin are dependent on cell surface Heparan Sulfate. J. Biol. Chem 281(21): 14813-14822. Clore, G. M. and Gronenborn, A. M. (1989). How accurately can interproton distances in macromoleculae really be determined by full relaxation matrix analysis of nuclear overhauser enhancement data? J. Magn. Reson. 84: 398-409. Cohen, A. R., Woods, D. F., Marfatia, S. M., Walther, Z., Chishti, A. H., Anderson, J. M. and Wood, D. F. (1998). Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells. J. Cell. Biol 142(1): 129-38. Cole, G. J. and Halfter, W. (1996). Agrin: an extracellular matrix heparan sulfate proteoglycan involved in cell interactions and synaptogenesis. Perspect. Dev. Neurobiol. 3(4): 359-371. Collins, P. and Ferrier, R. (1998). Monosaccharides, Their chemistry and their roles in natural products. Chichester, John Wiley & Sons. Coltrini, D., Rusnati, M., Zoppetti, G., Oreste, P., Grazioli, G., Naggi, A. and Presta, M. (1994). Differential effects of mucosal, bovine lung and chemically modified heparin on selected biological properties of fibroblast growth factor. Biochem. J. 303: 583-590. Conrad, H. E. (1998). Heparin binding proteins. San Diego, Academic press. Coombe, D. R. and Kett, W. C. (2005). Heparan sulfate-protein interactions: therapeutic potential through structure-function insights. Cell. Mol. Life Sci. 62(4): 410-424. Coutts, J. C. and Gallagher, J. T. (1995). Receptors for fibroblast growth factors. Immun. Cell. Biol. 73(6): 584-9. Cremer, D. (1984). On the correct usage of the Cremer-Pople puckering parameters as quantitative descriptors of ring shapes - a reply to recent criticism by Petit, Dillen and Geise. Acta. Cryst. B40: 498-500. Cremer, D. and Pople, J. A. (1975). A general definition of ring puckering coordinates. J. Am. Chem. Soc. 97: 1354-1358. Cros, S., Petitou, M., Sizun, P., Perez, S. and Imberty, A. (1997). Combined NMR and molecular modelling study of an Iduronic acid containing trisaccharide related to antithrombotic Heparin fragments. Bioorg. Med. Chem. 5(7): 1301-1309. 359 Danielsson, A., Raub, E., Lindahl, U. and Bjork, I. (1986). Role of ternary complexes, in which heparin binds both antithrombin and proteinase, in the acceleration of the reactions between antithrombin and thrombin or factor Xa. J. Biol. Chem. 261(33): 15467-73. Das, S. K., Mallet, J. M., Esnault, J., Driguez, P. A., Duchaussoy, P., Sizun, P., Herault, J. P., Herbert, J. M., Petitou, M. and Sinay, P. (2001). Synthesis of conformationally locked carbohydrates: a skew-boat conformation of L-iduronic acid governs the antithrombotic activity of heparin. Angew Chem Int Ed Engl 40: 1670-1673. David, G. (1993). Integral membrane heparan sulfate proteoglycans. FASEB. J. 7(11): 1023-30. De Cat, B. and David, G. (2001). Developmental roles of the glypicans. Sem. Cell. Develop. Biol. 12: 117-125. Deepa, S. S., Yamada, S., Zako, M., Goldberger, O. and Sugahara, K. (2004). Chondroitin sulfate chains on syndecan-1 and syndecan-4 from normal murine mammary gland epithelial cells are structurally and functionally distinct and cooperate with heparan sulfate chains to bind growth factors. A novel function to control binding of midkine, pleiotrophin, and basic fibroblast growth factor. J. Biol. Chem 279: 37368-37376. Desai, U. R. and Linhardt, R. J. (1995). Molecular weight of Heparin using 13C nuclear magnetic resonance spectroscopy. J. Pharm. Sci. 84(2): 212-215. Desai, U. R., Wang, H. M. and Linhardt, R. J. (1993). Specificity studies on the heparin lyases from Flavobacterium heparinum. Biochemistry. 32(32): 8140-5. Dhoot, G. K., Gustafsson, M. K., Ai, X., Sun, W., Standiford, D. M. and Emerson, J. C. P. (2001). Regulation of Wnt signalling and embryo patterning by an extracellular sulfatase. Science 293: 1663-1666. Dong, S., Cole, G. J. and Halfter, W. (2003). Expression of collagen XVIII and localization of its glycosaminoglycan attachment sites. J. Biol. Chem. 278(3): 1700-7. Duchesne, L., Tissot, B., Rudd, T. R., Dell, A. and Fernig, D. G. (2006). N-glycosylation of fibroblast growth factor receptor 1 regulates ligand and heparan sulfate coreceptor binding. J. Biol. Chem. 281(37): 27178-27189. Edge, A. S. and Spiro, R. G. (1985). Structural elucidation of glycosaminoglycans through characterization of disaccharides obtained after fragmentation by hydrazine-nitrous acid treatment. Arch. Biochem. Biophys. 240(2): 560-72. Eriksson, I., Sandback, D., Ek, B., Lindahl, U. and Kjellen, L. (1994). cDNA cloning and sequencing of mouse mastocytoma glucosaminyl N-deacetylase/Nsulfotransferase, an enzyme involved in the biosynthesis of heparin. J. Biol. Chem. 269(14): 10438-43. Esko, J. D. and Selleck, S. B. (2002). Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu. Rev. Biochem. 71: 435-71. Ethell, I. M., Hagihara, K., Miura, Y., Irie, F. and Yamaguchi, Y. (2000). Synbindin, a novel syndecan-2-binding protein in neuronal dendritic spines. J. Cell. Biol. 151(1): 53-68. 360 Faham, S., Hileman, R. E., Fromm, J. R., Linhardt, R. J. and Rees, D. C. (1996). Heparin structure and interactions with basic fibroblast growth factor. Science. 271(5252): 1116-20. Ferro, D. R., Provasoli, A., Ragazzi, M., Casu, B., Torri, G., Bossennec, V., Perly, B. and Sinay, P. (1990). Conformer populations of L-Iduronic acid residues in glycosaminoglycan sequences. Carbohydr. Res. 195: 157-167. Filmus, J. (2001). Glypicans in the growth control of cancer. Glycobiology. 11(3): 19R- 23R. Forsberg, E., Pejler, G., Ringvall, M., Lunderius, C., Tomasini_Johansson, B., Kusche_Gullberg, M., Eriksson, I., Ledin, J., Hellman, L. and Kjellen, L. (1999). Abnormal mast cells in mice deficient in a heparin-synthesizing enzyme. Nature. 400(6746): 773-6. Forster, M. J. and Mulloy, B. (1993). Molecular dynamics study of Iduronate ring conformation. Biopolymers 33: 575-588. Fritz, T. A., Gabb, M. M., Wei, G. and Esko, J. D. (1994). Two Nacetylglucosaminyltransferases catalyze the biosynthesis of heparan sulfate. J. Biol. Chem. 269(46): 28809-14. Gallagher, J. T. and Lyon, M. (2000). Molecular structure of heparan sulfate and interactions with growth factors and morphogens. Proteoglycans: structure, biology and molecular interactions. R. V. Iozzo. New York, Marcel Dekker Inc. New York: 27-59. Gallagher, J. T. and Walker, A. (1985). Molecular distinctions between heparan sulphate and heparin. Analysis of sulphation patterns indicates that heparan sulphate and heparin are separate families of N-sulphated polysaccharides. Biochem. J. 230(3): 665-74. Galliher, P. M., Cooney, C. L., Langer, R. and Linhardt, R. J. (1981). Heparinase production by Flavobacterium heparinum. Appl. Environ. Microbiol. 41(2): 360- 5. Gao, Y., M., L., Chen, W. and Simons, M. (2000). Synectin, syndecan-4 cytoplasmic domain binding PDZ protein, inhibits cell migration. J. Cell. Physiol. 184: 373- 379. Goodger, S. J. (2003). The role and structure of heparan sulfate in the regulation of FGF- 1 and FGF-2. School of Biological Sciences. Manchester, University of Manchester. PhD: 260. Griffin, C. C., Linhardt, R. J., Van Gorp, C. L., Toida, T., Hileman, R. E., Schubert, R. L. and Brown, S. E. (1995). Isolation and characterisation of heparan sulfate from crude porcine intestinal mucosal peptidoglycan heparin. Carbohydr. Res. 276: 183-197. Groffen, A. J., Buskens, C. A., van_Kuppevelt, T. H., Veerkamp, J. H., Monnens, L. A. and van_den_Heuvel, L. P. (1998). Primary structure and high expression of human agrin in basement membranes of adult lung and kidney. Eur. J. Biochem. 254(1): 123-8. Guerrini, M., Agulles, T., Bisio, A., Hricovini, M., Lay, L., Naggi, A., Poletti, L., Sturiale, L., Torri, G. and Casu, B. (2002). Minimal heparin/heparan sulfate 361 sequences for binding to fibroblast growth factor-1. Biochem. Biophys. Res. Commun. 292(1): 222-30. Guerrini, M., Bisio, A. and Torri, G. (2001). Combined quantitative (1)H and (13)C nuclear magnetic resonance spectroscopy for characterization of heparin preparations. Semin. Thromb. Hemost. 27(5): 473-82. Guimond, S., Maccarana, M., Olwin, B. B., Lindahl, U. and Rapraeger, A. C. (1993). Activating and inhibitory heparin sequences for FGF-2 (basic FGF). Distinct requirements for FGF-1, FGF-2, and FGF-4. J. Biol. Chem. 268(32): 23906-14. Guimond, S. E. and Turnbull, J. E. (1999). Fibroblast growth factor receptor signalling is dictated by specific heparan sulphate saccharides. Curr. Biol. 9: 1343-1346. Haasnoot, C. A. G., de Leeuw, F. A. A. M. and Altona, C. (1979). The relationship between proton-proton NMR coupling-constants and substituent electronegativities. 1. An empirical generalization of the Karplus equation. Tetrahedron 36: 2783-2792. Habuchi, H., Tanaka, M., Habuchi, O., Yoshida, K., Suzuki, H., Ban, K. and Kimata, K. (2000). The occurrence of three isoforms of heparan sulfate 6-O-sulfotransferase having different specificities for hexuronic acid adjacent to the targeted Nsulfoglucosamine. J. Biol. Chem. 275(4): 2859-68. Hagner Mcwhirter, A., Lindahl, U. and Li, J. (2000). Biosynthesis of heparin/heparan sulphate: mechanism of epimerization of glucuronyl C-5. Biochem. J. 347 Pt 1: 69-75. Hakanss
Depositing User: Users 4 not found.
Date Deposited: 20 Dec 2007
Last Modified: 06 Apr 2018 16:52
URI: http://eprints.hud.ac.uk/id/eprint/189

Downloads

Downloads per month over past year

Repository Staff Only: item control page

View Item View Item

University of Huddersfield, Queensgate, Huddersfield, HD1 3DH Copyright and Disclaimer All rights reserved ©