Nitric Oxide-inducible Expression of Heme Oxygenase-1 in Human Cells

Abstract

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These molecules are linear polysaccharides consisting of repeating disaccharide unit backbones onto which are superimposed specific modification patterns, most notably addition of sulfate groups. HS stands out as the family member with the most highly variable structure owing to the polymorphic nature of the highly sulfated sequences expressed within its chains. It is these sulfated structural motifs that are primarily responsible for the numerous protein binding and regulatory properties of HS 1,2. Over the past decade, our understanding of the functions of these molecules has shifted dramatically-from being seen as simply structural determinants of the extracellular matrix (ECM) to being key players in the regulatory network of the cell. HS chains are normally attached to 'core proteins' through a serine residue to form HS proteoglycans (HSPGs), which are strategically located at the cell surface and in the ECM (see Fig. 1; for a detailed review, see Ref. 2). Proteoglycans are glycoproteins with one or more GAG chains attached to the core protein. They include the syndecan family (four members in mammals) of transmembrane proteins, the glypican family of proteins (six members in mammals) attached to the cell membrane by a glycosylphosphatidylinositol (GPI) tail, and ECM proteins such as perlecan. There has been an increasing realization that specific sequences in the HS chains are designed for selective interactions with certain proteins 1 and that these interactions result in regulation of the protein activities. Together with the knowledge that cells can dynamically alter the structure of HS sequences, this has led to the view that HS functions as a new class of multifunctional cell regulator (for reviews, see chapters in Ref. 3). This review describes recent developments in this field and surveys the future prospects for understanding the mechanisms of functional specificity of these fascinating molecules. 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 Refs 4-7). 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 The heparan sulfates are a family of cell-surface and matrix polysaccharides with an incredible degree of structural diversity that are distributed widely in virtually all metazoan organisms. Recent genetic, biochemical and cell-biological studies have led to increased understanding of the biosynthetic mechanisms that produce these complex molecules, as well as their functional versatility in regulating protein activities. The dynamic expression of heparan sulfates with differing sugar sequences suggests a new concept in which the repertoire of sequences produced by a particular cell or tissue is designated its 'heparanome'. This review discusses recent developments and surveys emerging experimental strategies that hold promise for revealing the functional specificity and mechanisms of action of heparan sulfates as multifunctional cell regulators.