Expanding the Chondroitin Sulfate Glycoproteome — But How Far?

Abstract

Chondroitin sulfate proteoglycans (CSPGs) are found at cell surfaces and in connective tissues, where they interact with a multitude of proteins involved in various pathophysiological processes. From a methodological perspective, the identification of CSPGs is challenging, as the identification requires the combined sequencing of specific core proteins, together with the characterization of the CS polysaccharide modification(s). According to the current notion of CSPGs, they are often considered in relation to a functional role in which a given proteoglycan regulates a specific function in cellular physiology. Recent advances in glycoproteomic methods have, however, enabled the identification of numerous novel chondroitin sulfate core proteins, and their glycosaminoglycan attachment sites, in humans and in various animal models. In addition, these methods have revealed unexpected structural complexity even in the linkage regions. These findings indicate that the number and structural complexity of CSPGs are much greater than previously perceived. In light of these findings, the prospect of finding additional CSPGs, using improved methods for structural and functional characterizations, and studying novel sample matrices in humans and in animal models is discussed. Further, as many of the novel CSPGs are found in low abundance and with not yet assigned functions, these findings may challenge the traditional notion of defining proteoglycans. Therefore, the concept of proteoglycans is considered, discussing whether “a proteoglycan” should be defined mainly on the basis of an assigned function or on the structural evidence of its existence.

The Essential Role of Proteoglycans and Glycosaminoglycans in Odontogenesis

“…The various functions of proteoglycans largely stem from the enormous structural diversity of GAGs. The heterogeneity of GAGs relies on complex biosynthetic pathways involving more than 40 enzymes with a role in linkage formation, chain elongation, and modifications, including sulfation, deacetylation, and isomerization (Noborn et al 2021) (Fig. 1).…”

Spatiotemporal diversity and regulation of glycosaminoglycans in cell homeostasis and human disease

“…HS and CS/DS are linear polysaccharides that are assembled while attached to one of ∼77 known proteoglycan core proteins. These proteoglycans are differentially expressed in various tissues and cell types, and certain core proteins can also function as part-time proteoglycans, meaning they may exist with or without the GAG chains ( 15 , 16 ). These heterogeneous polysaccharides are biosynthesized in a nontemplate-driven manner by a family of enzymes encoded by nearly 40 genes ( 17 ).…”

Extracellular matrix guidance of autophagy: a mechanism regulating cancer growth

“…Yet another recent observation is the report that progranulin, a growth factor that interacts with perlecan [172], is a negative regulator of autophagy [243]. The playing field of proteoglycan research is expanding, given the discovery of novel proteoglycans using mass spectrometry [244] in Caenorhabditis elegans, and glycoproteomics approaches in both C. elegans and mammalian cells [245][246][247]. Intriguingly, some of these novel chondroitin sulfate proteoglycans are canonical prohormones, typically stored and secreted from granules of endocrine cells [248].…”