Trends in Cell Biology
ReviewHeparan sulfate: decoding a dynamic multifunctional cell regulator
Section snippets
Biosynthesis creates structurally diverse heparan sulfate sequences
The biosynthesis of HS occurs mainly in the Golgi apparatus and involves a complex set of enzyme reactions that first create a non-sulfated polysaccharide chain precursor and then modify it by a sequential series of reactions that superimpose complex patterns of sulfation at selective positions (see Box 1; for recent reviews, see 4., 5., 6., 7.). The crucial points to note are that the system is not template-driven and these reactions do not go to completion. This results in a high degree of
Heparan sulfates as multifunctional cell regulators
Bearing in mind the highly sulfated nature of HS, it is hardly surprising that it interacts with a wide variety of proteins. These include growth factors, enzymes, ECM proteins and proteins found on the surface of pathogens. The almost bewildering number of examples has led to the perception by some that the interactions are relatively nonspecific. This view is steadily giving way under the weight of evidence for interactions between specific consensus structural motifs in HS and many
Essential roles for HS in development
Recent striking evidence of an in vivo regulatory role for HS has come from genetic studies in Drosophila, Caenorhabditis elegans and mouse. Mutations or knockouts of HS biosynthetic enzymes or HSPG core proteins have been shown to dramatically perturb various aspects of development and indicate that HS has functional roles in cell–cell signalling and morphogenesis. Drosophila studies have been particularly revealing as genetic screens for functional mutations in signaling pathways involving
Decoding the messages in HS sequences
The potential informational content in HS sequences is truly vast and is translated into biological effects through interactions with protein ligands. A major impediment to progress in determining the ligand-specific sequences encoded in HS chains has been the lack of practical and direct sequencing methods. Previously, structural characterization relied on NMR spectroscopy (which requires milligrams of sample) or indirect analysis involving laborious and time-consuming enzymic and chemical
New strategies for revealing functional specificity
The past decade has seen a dramatic shift in our view of HS. We now have a clear picture of a molecule that is produced by a tightly regulated biosynthetic mechanism in order to perform distinct and diverse regulatory roles. Much current research is now aimed at increasing our understanding of the functional specificity of HS. Recently, a new array of approaches has begun to illuminate HS structure–function relationships, especially in relation to FGF signalling.
In order to study the link
Future challenges and prospects – exploring the ‘heparanome’
It is apparent that HS acts as a multifunctional regulator of protein activities through a range of different mechanisms dependent on specific HS–protein interactions. Emerging data on the diversity and dynamic synthesis of HS sequences indicate that we need a radically different mind set when thinking about these molecules in comparison to the sequences of proteins and DNA. An analogy can be drawn with the proteome, and we propose the concept of the ‘heparanome’ as a descriptor for the
Acknowledgements
We thank members of the Turnbull laboratory and collaborators for contributing to the work and critically reviewing the manuscript, and Kathy Drummond and Miriam Ford-Perriss for sharing unpublished results. The experimental work of the authors is supported by the Medical Research Council (Senior Research Fellowship to JET), The Royal Society, the European Union, and the Human Frontier Science Program. We apologize to those authors whose work we were unable to cite owing to space constraints.
References (53)
- et al.
Glycosaminoglycan–protein interactions: a question of specificity
Curr. Opin. Struct. Biol.
(1994) Regulated diversity of heparan sulfate
J. Biol. Chem.
(1998)Proteoglycans and pattern formation: sugar biochemistry meets developmental genetics
Trends Genet.
(2000)The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate
J. Biol. Chem.
(1998)- et al.
Molecular cloning and expression of a third member of the heparan sulfate/heparin GlcNAc N-deacetylase/N-sulfotransferase family
J. Biol. Chem.
(1999) The occurrence of three isoforms of heparan sulfate 6-O-sulfotransferase having different specificities for hexuronic acid adjacent to the targeted N-sulfoglucosamine
J. Biol. Chem.
(2000)Multiple isoforms of heparan sulfate D-glucosaminyl 3-O-sulfotransferase. Isolation, characterization, and expression of human cDNAs and identification of distinct genomic loci
J. Biol. Chem.
(1999)Molecular cloning and expression of Chinese hamster ovary cell heparan-sulfate 2-sulfotransferase
J. Biol. Chem.
(1997)Biosynthesis of heparin/heparan sulfate. cDNA cloning and expression of D-glucuronyl C5-epimerase from bovine lung
J. Biol. Chem.
(1997)Expression of heparan sulfate D-glucosaminyl 3-O-sulfotransferase isoforms reveals novel substrate specificities
J. Biol. Chem.
(1999)
Domain structure of heparan sulfates from bovine organs
J. Biol. Chem.
Cell surface syndecan-1 on distinct cell types differs in fine structure and ligand binding of its heparan sulfate chains
J. Biol. Chem.
Fine structure of heparan sulfate regulates syndecan-1 function and cell behavior
J. Biol. Chem.
Heparan sulfate undergoes specific structural changes during the progression from adenoma to carcinoma in vitro
J. Biol. Chem.
Metabolism of proteoglycans in rat ovarian granulosa cell culture: multiple intracellular degradative pathways and the effect of chloroquine
J. Biol. Chem.
Heparan sulfate proteoglycan synthesis and metabolism by mouse uterine epithelial cells cultured in vitro
J. Biol. Chem.
Age-dependent modulation of heparan sulfate structure and function
J. Biol. Chem.
Structural modification of fibroblast growth factor-binding heparan sulfate at a determinative stage of neural development
J. Biol. Chem.
Heparan sulfate mediates bFGF transport through basement membrane by diffusion with rapid reversible binding
J. Biol. Chem.
Heparin decreases the blood clearance of interferon-gamma and increases its activity by limiting the processing of its carboxyl-terminal sequence
J. Biol. Chem.
Cell surface heparan sulfate proteoglycans: selective regulators of ligand–receptor encounters
J. Biol. Chem.
Numbers, time and neocortical neuronogenesis: a general developmental and evolutionary model
Trends Neurosci.
Highly sensitive sequencing of the sulfated domains of heparan sulfate
J. Biol. Chem.
Fibroblast growth factor receptor signalling is dictated by specific heparan sulphate saccharides
Curr. Biol.
Heparan sulfate oligosaccharides require 6-O-sulfation for promotion of basic fibroblast growth factor mitogenic activity
J. Biol. Chem.
Interaction of heparan sulfate from mammary cells with acidic fibroblast growth factor (FGF) and basic FGF. Regulation of the activity of basic FGF by high and low affinity binding sites in heparan sulfate
J. Biol. Chem.
Cited by (413)
Scientific considerations in the regulatory approval of generic (or biosimilar) version of enoxaparin sodium – A lifesaving carbohydrate polymer
2023, Regulatory Toxicology and PharmacologyThe role of the cell surface glycocalyx in drug delivery to and through the endothelium
2022, Advanced Drug Delivery ReviewsVariability in the composition of porcine mucosal heparan sulfates
2022, Carbohydrate Polymers3-O-Sulfation induces sequence-specific compact topologies in heparan sulfate that encode a dynamic sulfation code
2022, Computational and Structural Biotechnology JournalA crosslinked dextran sulfate-chitosan nanoparticle for delivery of therapeutic heparin-binding proteins
2021, International Journal of PharmaceuticsCitation Excerpt :DS is homogeneously sulfated and contains 2.1–3.1 sulphonic groups per each glucose unit (sulfur content 17–20%). Heparin and heparan sulfate are heterogeneously sulfated in certain regions/domains of the molecules (Shriver et al., 2012; Turnbull et al., 2001), with an average sulphonic group content in heparin of 1.1 per monosaccharide (sulfur content 11.3–12.4%) (Aviezer et al., 1994; Ziegler and Seelig, 2008), and in heparan sulfate of 0.39 per monosaccharide (sulfur content 5.51%). ( Kuwabara et al., 2015) Thus, the overall sulfation density in these molecules is in the order of DS > heparin > heparan sulfate.