Sulfation patterns of glycosaminoglycans encode molecular recognition and activity

Although glycosaminoglycans contribute to diverse physiological processes1,2,3,4, an understanding of their molecular mechanisms has been hampered by the inability to access homogeneous glycosaminoglycan structures. Here, we assembled well-defined chondroitin sulfate oligosaccharides using a convergent, synthetic approach that permits installation of sulfate groups at precise positions along the carbohydrate backbone. Using these defined structures, we demonstrate that specific sulfation motifs function as molecular recognition elements for growth factors and modulate neuronal growth. These results provide both fundamental insights into the role of sulfation and direct evidence for a 'sulfation code' whereby glycosaminoglycans encode functional information in a sequence-specific manner analogous to that of DNA, RNA and proteins.

[1]  R. An Chondroitinase ABC promotes functional recovery after spinal cord injury , 2002 .

[2]  Ten Feizi,et al.  Carbohydrate microarrays - a new set of technologies at the frontiers of glycomics. , 2003, Current opinion in structural biology.

[3]  S. L. Mayo,et al.  DREIDING: A generic force field for molecular simulations , 1990 .

[4]  Sherry M. Tsai,et al.  A chondroitin sulfate small molecule that stimulates neuronal growth. , 2004, Journal of the American Chemical Society.

[5]  C. V. Boeckel,et al.  Syntheses of heparin - like pentamers containing “opened” uronic acid moieties , 1990 .

[6]  A. Plaas,et al.  Glycosaminoglycan Sulfation in Human Osteoarthritis , 1998, The Journal of Biological Chemistry.

[7]  P. Bjorkman,et al.  Tolerization of adult mice to immunodominant proteins before monoclonal antibody production. , 1999, Journal of immunological methods.

[8]  J. Jacquinet,et al.  Multigram syntheses of the disaccharide repeating units of chondroitin 4- and 6-sulfates. , 1998, Carbohydrate research.

[9]  A. Habeeb,et al.  Determination of free amino groups in proteins by trinitrobenzenesulfonic acid. , 1966, Analytical biochemistry.

[10]  Robert J. Linhardt,et al.  Heparin—Protein Interactions , 2002 .

[11]  Michael J. Hansen,et al.  Semaphorin 5A Is a Bifunctional Axon Guidance Cue Regulated by Heparan and Chondroitin Sulfate Proteoglycans , 2004, Neuron.

[12]  J. Shioi,et al.  Appican, the Proteoglycan Form of the Amyloid Precursor Protein, Contains Chondroitin Sulfate E in the Repeating Disaccharide Region and 4-O-Sulfated Galactose in the Linkage Region* , 2001, The Journal of Biological Chemistry.

[13]  P. Bovolenta,et al.  Developmental distribution of glycosaminoglycans in embryonic rat brain: relationship to axonal tract formation. , 1996, Journal of neurobiology.

[14]  J. Jacquinet,et al.  Syntheses of chondroitin 4- and 6-sulfate pentasaccharide derivatives having a methyl beta-D-glucopyranosiduronic acid at the reducing end. , 2000, Carbohydrate research.

[15]  A. Skoff,et al.  Nerve growth factor regulates substance P in adult sensory neurons through both TrkA and p75 receptors , 2006, Experimental Neurology.

[16]  Nobuyuki Itoh,et al.  Structural and Functional Characterization of Oversulfated Chondroitin Sulfate/Dermatan Sulfate Hybrid Chains from the Notochord of Hagfish , 2004, Journal of Biological Chemistry.

[17]  F. Matsui,et al.  Developmental changes in the biochemical and immunological characters of the carbohydrate moiety of neuroglycan C, a brain-specific chondroitin sulfate proteoglycan , 2003, Glycoconjugate Journal.

[18]  Daniel T. Mainz,et al.  New pseudospectral algorithms for electronic structure calculations: Length scale separation and analytical two‐electron integral corrections , 1994 .

[19]  Sharon Brunett,et al.  Molecular dynamics for very large systems on massively parallel computers: The MPSim program , 1997 .

[20]  Robert J Linhardt,et al.  Liquid Chromatography/Mass Spectrometry Sequencing Approach for Highly Sulfated Heparin-derived Oligosaccharides* , 2004, Journal of Biological Chemistry.

[21]  I. K. Moiseev,et al.  Synthesis of Novel Adamantylalkoxyurea Derivatives from 2-(1-Adamantylimino)-1,3-oxathiolane , 1997 .

[22]  P. Seeberger,et al.  Microarrays of synthetic heparin oligosaccharides. , 2006, Journal of the American Chemical Society.

[23]  W. Goddard,et al.  Charge equilibration for molecular dynamics simulations , 1991 .

[24]  A L Pearlman,et al.  Thalamocortical axons extend along a chondroitin sulfate proteoglycan- enriched pathway coincident with the neocortical subplate and distinct from the efferent path , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[25]  T. Tsumoto,et al.  Long-Term Depression Is Not Induced by Low-Frequency Stimulation in Rat Visual Cortex In Vivo: A Possible Preventing Role of Endogenous Brain-Derived Neurotrophic Factor , 2003, The Journal of Neuroscience.

[26]  F. Seil,et al.  TrkB Receptor Ligands Promote Activity-Dependent Inhibitory Synaptogenesis , 2000, The Journal of Neuroscience.

[27]  N. Perrimon,et al.  Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion , 1998, Nature.

[28]  Zachary Shriver,et al.  Roles of heparan-sulphate glycosaminoglycans in cancer , 2002, Nature Reviews Cancer.

[29]  T. Muramatsu,et al.  Neuronal Cell Adhesion, Mediated by the Heparin-binding Neuroregulatory Factor Midkine, Is Specifically Inhibited by Chondroitin Sulfate E , 2000, The Journal of Biological Chemistry.

[30]  E. Huang,et al.  Neurotrophins: roles in neuronal development and function. , 2001, Annual review of neuroscience.

[31]  T. Muramatsu Midkine and pleiotrophin: two related proteins involved in development, survival, inflammation and tumorigenesis. , 2002, Journal of biochemistry.

[32]  C. Holt,et al.  Sugar Codes for Axons? , 2005, Neuron.

[33]  J. Buchanan-Smith,et al.  A colorimetric method for the quantitation of uronic acids and a specific assay for galacturonic acid. , 1992, Analytical biochemistry.

[34]  A. Lander,et al.  Interactions of neural glycosaminoglycans and proteoglycans with protein ligands: assessment of selectivity, heterogeneity and the participation of core proteins in binding. , 1999, Glycobiology.

[35]  Injae Shin,et al.  Carbohydrate chips for studying high-throughput carbohydrate-protein interactions. , 2004, Journal of the American Chemical Society.

[36]  H. Kitagawa,et al.  Developmental Regulation of the Sulfation Profile of Chondroitin Sulfate Chains in the Chicken Embryo Brain* , 1997, The Journal of Biological Chemistry.

[37]  J. Turnbull,et al.  Structural Modification of Fibroblast Growth Factor-binding Heparan Sulfate at a Determinative Stage of Neural Development* , 1998, The Journal of Biological Chemistry.

[38]  Shuhei Yamada,et al.  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 , 2004, Journal of Biological Chemistry.

[39]  N. Perrimon,et al.  Developmental cell biology: Heparan sulphate proteoglycans: the sweet side of development , 2005, Nature Reviews Molecular Cell Biology.

[40]  R. Linhardt,et al.  Recent chemical and enzymatic approaches to the synthesis of glycosaminoglycan oligosaccharides. , 2003, Current medicinal chemistry.