Abstract
BackgroundIncreasing evidence has revealed important roles for complex glycans as mediators of normal and pathological processes. Glycosaminoglycans are a class of glycans that bind and regulate the function of a wide array of proteins at the cell-extracellular matrix interface. The specific sequence and chemical organization of these polymers likely define function; however, identification of the structure-function relationships of glycosaminoglycans has been met with challenges associated with the unique level of complexity and the nontemplate-driven biosynthesis of these biopolymers.Methodology/Principal FindingsTo address these challenges, we have devised a computational approach to predict fine structure and patterns of domain organization of the specific glycosaminoglycan, heparan sulfate (HS). Using chemical composition data obtained after complete and partial digestion of mixtures of HS chains with specific degradative enzymes, the computational analysis produces populations of theoretical HS chains with structures that meet both biosynthesis and enzyme degradation rules. The model performs these operations through a modular format consisting of input/output sections and three routines called chainmaker, chainbreaker, and chainsorter. We applied this methodology to analyze HS preparations isolated from pulmonary fibroblasts and epithelial cells. Significant differences in the general organization of these two HS preparations were observed, with HS from epithelial cells having a greater frequency of highly sulfated domains. Epithelial HS also showed a higher density of specific HS domains that have been associated with inhibition of neutrophil elastase. Experimental analysis of elastase inhibition was consistent with the model predictions and demonstrated that HS from epithelial cells had greater inhibitory activity than HS from fibroblasts.Conclusions/SignificanceThis model establishes the conceptual framework for a new class of computational tools to use to assess patterns of domain organization within glycosaminoglycans. These tools will provide a means to consider high-level chain organization in deciphering the structure-function relationships of polysaccharides in biology.
Highlights
Complex glycans such as glycosaminoglycans (GAGs) are rapidly becoming appreciated as major regulators of cell function throughout the animal kingdom [1,2,3]
The experimental data consisted of the total disaccharide composition after digestion with heparin lyases I, II, and III (Table 1) and the percentage of each disaccharide released after sequential-like digestions with heparin lyases III, I, and II (Table 2)
Three groups (D0A0, D0A6, and D2S0) in Table 2 were chosen for comparison with the simulated disaccharide release, and practical tolerances for the breakdown constraints were set at D0A0 62%–4%, D0A6 620%, and D2S0 60% for each of the first two digestion steps
Summary
Complex glycans such as glycosaminoglycans (GAGs) are rapidly becoming appreciated as major regulators of cell function throughout the animal kingdom [1,2,3]. The GAG chains of proteoglycans have been shown to play important roles in mediating cell-extracellular matrix interactions, extracellular matrix structure and function, and cell-cell communication principally through the ability of GAGs to bind to a wide range of proteins [4,5]. Heparan sulfate (HS), the most structurally diverse GAG class, has been implicated in countless normal and pathological biological processes [1,3,6,7]. Increasing evidence has revealed important roles for complex glycans as mediators of normal and pathological processes. Glycosaminoglycans are a class of glycans that bind and regulate the function of a wide array of proteins at the cell-extracellular matrix interface. The specific sequence and chemical organization of these polymers likely define function; identification of the structure-function relationships of glycosaminoglycans has been met with challenges associated with the unique level of complexity and the nontemplate-driven biosynthesis of these biopolymers
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