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Chemical Approaches to Deciphering the Glycosaminoglycan Code Cristal I Gama and Linda C Hsieh-Wilson

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Chemical Approaches to Deciphering the Glycosaminoglycan Code Cristal I Gama and Linda C Hsieh-Wilson Chemical approaches to deciphering the glycosaminoglycan code Cristal I Gama and Linda C Hsieh-Wilson Glycosaminoglycans are sulfated biopolymers with rich saminoglycans. We also discuss the potential for syn- chemical diversity and complex functions in vivo, contributing thetic, chemoenzymatic and technological approaches to processes ranging from cell growth and neuronal to advance a molecular-level understanding of this impor- development to viral invasion and neurodegenerative disease. tant class of biopolymers. Recent studies suggest that glycosaminoglycans may encode information in the form of a ‘sulfation code,’ whereby discrete The chemical diversity of glycosaminoglycans modifications to the polysaccharide backbone may direct the Glycosaminoglycans are composed of repeating disac- location or activities of proteins. charide subunits that are assembled into linear polysac- charide chains (Figure 1). These polysaccharides are Addresses often covalently attached to proteoglycan proteins at Howard Hughes Medical Institute, Division of Chemistry and Chemical the cell surface or in the extracellular matrix. There Engineering, California Institute of Technology, 1200 East California are several major classes of glycosaminoglycans, including Boulevard, Pasadena, CA 91125, USA heparan sulfate (HS) and heparin, chondroitin sulfate Corresponding author: Hsieh-Wilson, Linda C ([email protected]) (CS), dermatan sulfate and keratan sulfate, which differ in their core disaccharide subunit. HS and heparin contain D-glucosamine (GlcN) and either D-glucuronic acid Current Opinion in Chemical Biology 9 2005, :1–11 (GlcA) or L-iduronic acid (IdoA) subunits joined by This review comes from a themed issue on a(1,4) and b(1,4) linkages. CS has N-acetylgalactosamine Biopolymers (GalNAc) and GlcA subunits and alternating b(1,3) and Edited by Scott A Strobel and Tom W Muir b(1,4) linkages. Diverse sulfation patterns are generated in vivo through 1367-5931/$ – see front matter extensive modification of the carbohydrate backbone [3]. # 2005 Elsevier Ltd. All rights reserved. For example, sulfation of HS and heparin can occur at the C2 hydroxyl of IdoA and the C3 and C6 hydroxyls of DOI 10.1016/j.cbpa.2005.10.003 GlcN. The C2 amine can also be either sulfated, acety- lated or remain unmodified. Although HS and heparin are structurally related, HS has greater overall chemical com- Introduction plexity, exhibiting more varied sulfation patterns, lower Glycosaminoglycans are a family of sulfated polysacchar- IdoA content and longer polysaccharide chains. More- ides involved in diverse biological processes such as over, HS is ubiquitously expressed in vivo and has a neuronal development, tumor growth and metastasis, broader range of physiological targets than heparin, which viral invasion and spinal cord injury [1–3]. For example, is localized primarily to specialized granule cells. Diverse glycosaminoglycans modulate key signaling pathways sulfation motifs are also found on CS, with sulfation essential for proper cell growth and angiogenesis [1,2]. occurring at each of the free hydroxyls [7]. As a result, They are also important for axon pathfinding in the a simple tetrasaccharide of CS has the potential to encode developing brain and have been linked to the pathology 256 sulfation sequences, whereas an HS tetrasaccharide, of Alzheimer’s disease [4,5,6]. The remarkable ability of which has greater complexity due to the presence of IdoA glycosaminoglycans to regulate various processes is only and N-sulfation, can display over 2000 sulfation motifs. beginning to be understood at a molecular level. Increas- Although it remains to be seen whether all of these ing evidence suggests that glycosaminoglycans encode possible sulfation patterns occur in vivo, a large number information in the form of a ‘sulfation code.’ Namely, of distinct sulfated structures have been identified to date discrete sulfation motifs along the carbohydrate backbone [3,7]. carry instructions to direct proteins and regulate complex processes such as neuronal wiring. Deciphering this code On a macromolecular level, HS and CS polysaccharides and the mechanisms by which it coordinates biological exhibit various chain lengths (10 to 100 disaccharide events is crucial for understanding diverse aspects of units) and clustered regions of high or low sulfation [3]. biology and could reveal new therapeutic opportunities. Structural studies have shown that glycosaminoglycans adopt helical structures whose pitch can vary with the In this review, we describe evidence for the sulfation code associated counterion [8,9]. Moreover, the conformational in the context of heparan and chondroitin sulfate glyco- flexibility of the pyranose ring of IdoA, which exists in www.sciencedirect.com Current Opinion in Chemical Biology 2005, 9:1–11 COCHBI 293 2 Biopolymers Figure 1 proteins. One of the most studied examples is the binding of HS to the fibroblast growth factors (FGFs). The FGFs comprise a large family of growth factors (23 members to date) and have been shown to have crucial roles in morphogenesis, development, angiogenesis and wound healing [15]. They induce the dimerization of FGF receptor tyrosine kinases (FGFRs), thereby activating intracellular signaling pathways. Two distinct models have been proposed to explain the essential contribution of HS to FGF–FGFR signaling. A crystal structure of the HS–FGF2–FGFR1 complex obtained by Schlessinger et al.[8] suggests that two ternary complexes of HS– FGF–FGFR come together with the non-reducing ends of each sugar chain facing one another upon activation (Figure 2a). By contrast, the HS–FGF1–FGFR2 structure of Pellegrini et al.[16] suggests that a single HS chain initiates the assembly of two FGF–FGFR complexes Representative classes of glycosaminoglycans, with potential À À (Figure 2b). Although these models propose distinct roles sites of sulfation indicated. R = SO3 or H; R1 =SO3 , H or Ac; n=10–100. for HS in coordinating receptor dimerization, both agree on the formation of an activated FGF–FGFR–HS com- plex. equilibrium between different chair and skew-boat con- formations when sulfated at the C2 position, has been Importantly, the specific sulfation pattern of HS appears postulated to enhance the specificity of HS for its protein to be crucial for FGF binding and assembly of the targets [3]. Thus, the combination of sequence, charge complex. Structural analyses have shown that many of distribution, sugar conformation and three-dimensional the interactions between HS and the FGFs involve salt structure endows glycosaminoglycans with rich structural bridges and hydrogen-bonding contacts between the diversity. sulfate and carboxylate groups of the oligosaccharide with polar residues of the protein [17]. Optimal van der Waals The potential ‘sulfation code’: implications for contacts and the flexibility of HS chains further enhance growth factor signaling and neuronal wiring the interaction [18]. Interestingly, none of the residues in Evidence suggests that the fine structure of glycosami- the heparin-binding region, including the polar side noglycans is crucial for their functions in vivo. Genetic chains, are completely conserved throughout the FGF studies have established the importance of various sulfo- family [17]. This raises the intriguing possibility that transferase enzymes in the glycosaminoglycan biosyn- variations in HS sequence or sulfation pattern might thetic pathway. For example, deletion of an HS 2-O- specify the binding of particular FGFs, enabling the sulfotransferase gene in mice led to complete failure of selective activation of signaling pathways. Consistent kidney development, and mutation of the N-deacetylase– with this view, biochemical studies have shown that N-sulfotransferase gene in Drosophila inhibited growth FGF2 requires 2-O-sulfation but not 6-O-sulfation for factor signaling and disrupted embryonic development HS binding, whereas FGF10 has the reverse preference, [5,10]. Consistent with their essential roles, the sulfation and FGF1 requires both 2-O-sulfation and 6-O-sulfation patterns of glycosaminoglycans are tightly regulated in [19]. Distinct sulfation preferences are also exhibited by vivo. Distinct sulfated forms are associated with particular the FGFRs; for example, 6-O-sulfation was required for tissues: for example, differentially sulfated CS motifs are FGFR2 IIIb but not FGFR1 activation [20]. Unfortu- localized to specific brain regions and found along axonal nately, the heterogeneity of biochemical HS preparations growth tracts [11,12]. The sulfation patterns of HS and CS has made it difficult to examine specific sulfation are also altered during embryonic brain development, as sequences. As discussed below, it is anticipated that are specific sulfotransferase activities [13,14]. Further- homogeneous oligosaccharide libraries of defined more, distinct HS motifs have been linked to the devel- sequence will provide additional insights into the impor- opment of several diseases, including the pathology of tance of the sulfation code. Resolution of the code and Alzheimer’s disease and cancer metastasis [2,6]. precise activation mechanism will be crucial for under- standing growth factor signaling, and may reveal common The molecular mechanisms by which glycosaminogly- mechanistic themes utilized by both HS and CS glyco- cans contribute to these biological events are only begin- saminoglycans. ning to be understood. However, many studies suggest that glycosaminoglycans coordinate complex processes by Recent studies have
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