Chondroitin Sulfate/Dermatan Sulfate-Protein Interactions and Their Biological Functions in Human Diseases: Implications and Analytical Tools

Abstract

Chondroitin sulfate (CS) and dermatan sulfate (DS) are linear anionic polysaccharides that are widely present on the cell surface and in the cell matrix and connective tissue. CS and DS chains are usually attached to core proteins and are present in the form of proteoglycans (PGs). They not only are important structural substances but also bind to a variety of cytokines, growth factors, cell surface receptors, adhesion molecules, enzymes and fibrillary glycoproteins to execute series of important biological functions. CS and DS exhibit variable sulfation patterns and different sequence arrangements, and their molecular weights also vary within a large range, increasing the structural complexity and diversity of CS/DS. The structure-function relationship of CS/DS PGs directly and indirectly involves them in a variety of physiological and pathological processes. Accumulating evidence suggests that CS/DS serves as an important cofactor for many cell behaviors. Understanding the molecular basis of these interactions helps to elucidate the occurrence and development of various diseases and the development of new therapeutic approaches. The present article reviews the physiological and pathological processes in which CS and DS participate through their interactions with different proteins. Moreover, classic and emerging glycosaminoglycan (GAG)-protein interaction analysis tools and their applications in CS/DS-protein characterization are also discussed.

In-Depth Molecular Dynamics Study of All Possible Chondroitin Sulfate Disaccharides Reveals Key Insight into Structural Heterogeneity and Dynamism

“…CS has been found to have major roles in neurobiology [ 9 , 12 , 13 , 14 ]. Although oligosaccharide sequences with high selectivity for target proteins have yet to be identified, CS-E (GalNAc4S6S) has been found to be a powerful neuronal modulator [ 2 , 15 , 16 , 17 ]. Likewise, our recent computational work identified dual site interactions between TGFβ and distinct CS oligosaccharides [ 25 ].…”

“…Sulfated glycosaminoglycans (GAGs) are increasingly being recognized as contributing to biological functions in either their covalently-bound form, as a part of proteoglycans on cell surfaces, or in free solution form, as endogenous polysaccharides or oligosaccharides in biological fluids [ 1 , 2 , 3 ]. Structurally, multiple features make GAGs unique, including a high level of sulfation, a variable sulfation pattern, and different inter-glycosidic linkages.…”

Heterologous production of chondroitin

“…In higher animals, different types of GAGs can occur in different proportions and sizes depending for example on the animal, tissue, age or diet. GAG type Disaccharide repeat Natural sources Biological functions References CS-A GlcA(β1–3)GalNAc(4S)(β1–4) Dogfish, shark and whale cartilage; human, bovine, porcine and chicken cartilaginous tissues mediates malaria-infected erythrocytes adhesion; negatively regulates axonal guidance and growth; activates metastatic cascate [ 13 , 22 , 38 , 39 , 40 ] DS (CS-B) GlcA/IdoA(2S)(β/α1–3)GalNAc(4S)(β1–4) Animal skin/hide, cornea, cartilage, heart valve, tendons, blood vessels, and bone regulates growth factors activity; has anticoagulant activity; promotes proliferation of serveral cell lines; mediates homeostasis, tumorigenesis, infection, wound repair, collagen organization, fibrosis and stabilization of the basement membrane [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ] CS-C GlcA(β1–3)GalNAc(6S)(β1–4) Dogfish and shark cartilage; human, bovine, porcine and chicken cartilaginous tissues may promote progression of epilepsy; neuroprotective properties in Alzheimer's disease [ 13 , 38 , 41 , 42 , 43 ] CS-D GlcA(2S)(β1–3)GalNAc(6S)(β1–4) Shark cartilage; animal brain promotes neuron growth; interacts with humoral factors [ 22 , 44 , 45 , 46 ] CS-E GlcA(β1–3)GalNAc(4, 6diS)(β1–4) Squid cartilage; animal lung mediates angiogenesis; acts as cell surface receptor for herpes virus; modulates humoral factors; stimulates neurite outgrowth; promotes neural stem cells proliferation; mediates osteogenic differentiation [ 22...…”

Dermatan Sulfate Affects Breast Cancer Cell Function via the Induction of Necroptosis

“…Because of the composition of the disaccharide units, which build its po-lymeric linear chains, DS belongs to the chondroitin/dermatan subclass of the sulfated glycosaminoglycan (GAG) family. In fact, DS is a copolymer of two types of disaccharide units from which one is composed of N-acetylgalactosamine (GalNAc) and glucoronate (GlcA) residues while the other contains GalNAc and iduronate (IdoA) residues [ 1 ]. The former unit is not only present in DS but also in the chondroitin sulfate (CS) chains, in which it is the only structural element.…”