Site-specific glycosylation of proteoglycans: A revisited frontier in proteoglycan research

Proteoglycans (PGs), a class of carbohydrate-modified proteins, are present in essentially all metazoan organisms investigated to date. PGs are composed of glycosaminoglycan (GAG) chains attached to various core proteins and are important for embryogenesis and normal homeostasis. PGs exert many of their func-tions via their GAG chains and understanding the details of GAG-ligand interactions has been an essential part of PG research. Although PGs are also involved in many diseases, the number of GAG-related drugs used in the clinic is yet very limited, indicating a lack of detailed structure-function understanding. Structural analysis of PGs has traditionally been obtained by first separating the GAG chains from the core proteins, after which the two components are analyzed separately. While this strategy greatly facilitates the analysis, it precludes site-specific information and introduces either a GAG or a core protein perspective on the data interpretation. Mass-spectrometric (MS) glycoproteomic approaches have recently been introduced, provid-ing site-specific information on PGs. Such methods have revealed a previously unknown structural complex-ity of the GAG linkage regions and resulted in identification of several novel CSPGs and HSPGs in humans and in model organisms, thereby expanding our view on PG complexity. In light of these findings, we discuss here if the use of such MS-based techniques, in combination with various functional assays, can also be used to expand our functional understanding of PGs. We have also summarized the site-specific information of all human PGs known to date, providing a theoretical framework for future studies on site-specific func-tional analysis of PGs in human pathophysiology.(c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Automated summary

Proteoglycans are carbohydrate-modified proteins present in metazoan organisms. Their glycosaminoglycan (GAG) chains play important functional roles, but the detailed understanding of their structure and function is limited. Mass-spectrometric analysis provides site-specific information on proteoglycans and reveals their structural complexity. Combining functional assays with mass-spectrometric techniques can expand our understanding of proteoglycan function.