Abstract
Glycosaminoglycans (GAGs) are a family of linear and negatively charged polysaccharides that exist ubiquitously on the human cell surface as well as in the extracellular matrix. GAGs interact with a wide range of proteins, including proteases, growth factors, cytokines, chemokines and adhesion molecules, enabling them to mediate many physiological processes, such as protein function, cellular adhesion and signaling. GAG-protein interactions participate in and intervene in a variety of human diseases, including cardiovascular disease, infectious disease, neurodegenerative diseases and tumors. The breakthrough in analytical tools and approaches during the last two decades has facilitated a greater understanding of the importance of GAG-protein interactions and their roles in human diseases. This review focuses on aspects of the molecular basis and mechanisms of GAG-protein interactions involved in human disease. The most recent advances in analytical tools, especially mass spectrometry-based GAG sequencing and binding motif characterization methods, are introduced. An update of selected families of GAG binding proteins is presented. Perspectives on development of novel therapeutics targeting specific GAG-protein interactions are also covered in this review.
Highlights
COVID-19 disease, caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), has led to medical and economic disruptions worldwide
These studies have emphasized the importance of the interactions between glycosaminoglycans (GAGs) and proteins in disease and their roles as novel therapeutic targets, these interactions have been studied for decades but still lag behind the study of protein-protein and protein-nucleic acid interactions due to the structural complexity of GAGs and limitations of analytical tools
The structures and antibody binding sites of dengue virus E protein have been elucidated, and the results showed that specific carbohydrate residues with sulfation are common structures shared by chondroitin sulfate (CS)-E and heparin and could be essential determinants for controlling dengue virus entry mediated by the E protein (Kato et al, 2010)
Summary
COVID-19 disease, caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), has led to medical and economic disruptions worldwide. Some chemokines can be induced during an immune response to promote cells of the immune system to reach the infection site, while others participate in controlling the migration of cells during normal tissue maintenance or development processes (Mantovani et al, 2006) These proteins interact with G protein-linked transmembrane receptors (called chemokine receptors) to exert their biological effects, including selective recruitment and activation of cells during inflammation, stimulation of leukocyte degranulation, and promotion of angiogenesis or angiostasis (Crijns et al, 2020). The binding of heparin to neutrophil elastase, a serine protease, is involved in inflammation and pulmonary diseases, and targeting their binding site has led to discovering promising synthetic mimetics to treat cystic fibrosis (Morla et al, 2019) Both specific and nonspecific interactions in protein/ glycosaminoglycan associations reconcile the two opposing views that emphasize either the dominance of structural complementarity, similar to that encountered in protein/ protein interactions, or electrostatic forces. This work can be greatly facilitated by analytical tools that provide detailed information on the interactions between candidate drugs and their therapeutic targets
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