Structural Insights into Biological Roles of Protein-Glycosaminoglycan Interactions

Abstract

The extracellular environment is largely comprised of complex polysaccharides, which were historically considered inert materials that hydrated the cells and contributed to the structural scaffolds. Recent advances in development of sophisticated analytical techniques have brought about a dramatic transformation in understanding the numerous biological roles of these complex polysaccharides. Glycosaminoglycans (GAGs) are a class of these polysaccharides, which bind to a wide variety of proteins and signaling molecules in the cellular environment and modulate their activity, thus impinging on fundamental biological processes. Despite the importance of GAGs modulating biological functions, there are relatively few examples that demonstrate specificity of GAG-protein interactions, which in turn define the structure-function relationships of these polysaccharides. Focusing on heparin/heparan (HSGAGs) and chondroitin/dermatan sulfate (CSGAGs), this review provides structural insights into the oligosaccharide-protein interactions and discusses some key and challenging aspects of understanding GAG structure-function relationships.

Molecular structure of basic oligomeric building units of heparan-sulfate glycosaminoglycans

“…The solid-state structure of bound pentasaccharide can be affected by the so-called packing effects, which can distort the structure. The published cocrystal structures of pentasaccharide with proteins have highlighted the ionic interactions between specific anionic sulfate and carboxyl moieties of pentasaccharide with the basic cationic amino acid residues of binding site on the protein [8,12,51,52]. However, ionic contacts only are not sufficient to explain the optimal structural fit of pentasaccharide to the binding site of protein.…”

“…These residues are substituted with N-or O-sulfate groups with various degrees of substitution. The chemical heterogeneity of heparin in terms of its sulfation pattern and backbone chemical structure facilitates binding to a variety of proteins such as growth factors, enzymes, and morphogenes [8]. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups.…”

Anticoagulant heparan sulfate: structural specificity and biosynthesis

“…Decoding the nature of the interactions between HS and associated proteins has attracted considerable interest to delineate the involvement of HS in these important biological functions at the molecular level (6,7). The prevailing hypothesis is that a HS polysaccharide with specific sulfation patterns determines the binding affinity and the extent of the activation of a target protein.…”

Detection of a Non-animal Source of Glycosaminoglycans from Edible Mushrooms in Northern Thailand

“…Other sulfated GAGs, such as heparan sulfate and dermatan sulfate, are also found in cartilage and several tissues (Heinegård and Axelsson, 1977;Gandhi and Mancera, 2008). These GAGs have distinct biological functions; for instance, heparan sulfate plays an essential role as co-receptors for various receptor tyrosine kinases (Miserocchi et al, 2001), while chondroitin sulfate can prevent and maintain the structural-functional activity of cartilage during inflammation (Takagaki et al, 2002;Raman et al, 2005). In addition, chondroitin sulfate, as nutraceuticals or prescribed drugs in combination with glucosamine (GlcN) sulfate, has been increasingly employed to treat the symptoms of osteoarthritis and osteoarthrosis (Bishnoi et al, 2016).…”