HS, an Ancient Molecular Recognition and Information Storage Glycosaminoglycan, Equips HS-Proteoglycans with Diverse Matrix and Cell-Interactive Properties Operative in Tissue Development and Tissue Function in Health and Disease

Abstract

Heparan sulfate is a ubiquitous, variably sulfated interactive glycosaminoglycan that consists of repeating disaccharides of glucuronic acid and glucosamine that are subject to a number of modifications (acetylation, de-acetylation, epimerization, sulfation). Variable heparan sulfate chain lengths and sequences within the heparan sulfate chains provide structural diversity generating interactive oligosaccharide binding motifs with a diverse range of extracellular ligands and cellular receptors providing instructional cues over cellular behaviour and tissue homeostasis through the regulation of essential physiological processes in development, health, and disease. heparan sulfate and heparan sulfate-PGs are integral components of the specialized glycocalyx surrounding cells. Heparan sulfate is the most heterogeneous glycosaminoglycan, in terms of its sequence and biosynthetic modifications making it a difficult molecule to fully characterize, multiple ligands also make an elucidation of heparan sulfate functional properties complicated. Spatio-temporal presentation of heparan sulfate sulfate groups is an important functional determinant in tissue development and in cellular control of wound healing and extracellular remodelling in pathological tissues. The regulatory properties of heparan sulfate are mediated via interactions with chemokines, chemokine receptors, growth factors and morphogens in cell proliferation, differentiation, development, tissue remodelling, wound healing, immune regulation, inflammation, and tumour development. A greater understanding of these HS interactive processes will improve therapeutic procedures and prognoses. Advances in glycosaminoglycan synthesis and sequencing, computational analytical carbohydrate algorithms and advanced software for the evaluation of molecular docking of heparan sulfate with its molecular partners are now available. These advanced analytic techniques and artificial intelligence offer predictive capability in the elucidation of heparan sulfate conformational effects on heparan sulfate-ligand interactions significantly aiding heparan sulfate therapeutics development.

Kaposi’s sarcoma-associated herpesvirus glycoprotein K8.1 is critical for infection in a cell-specific manner and functions at the attachment step on keratinocytes

“…5 B). It should also be noted that heparan sulfate proteoglycans contain a highly complex mixture of sulfated sugars that may differ between cells (reviewed in (40)) and that the preferred heparan sulfate moieties can be quite specific, as was also observed for gH of KSHV (36).…”

Endothelial Glycocalyx in Aging and Age-related Diseases

“…There is a positive correlation between levels of HA in CSF and the CSF/ serum albumin ratio, an indicator of BBB integrity, in patients with vascular dementia and AD [ 107 ]. Furthermore, GAGs and PGs play pivotal roles in neuronal cell development and function [ 108 , 109 ]. HSPGs are formed by the binding of HS to PGs [ 110 ].…”

The Glycosaminoglycan Side Chains and Modular Core Proteins of Heparan Sulphate Proteoglycans and the Varied Ways They Provide Tissue Protection by Regulating Physiological Processes and Cellular Behaviour

“…Several excellent reviews on extracellular and cell surface HS–PGs exist in the literature. The interested reader is referred to these for further information [ 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 ]. In this review, the more important aspects of HS interactive components with representative examples of HS–PGs, such as perlecan and the syndecan, will be covered.…”