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 functions 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, providing site-specific information on PGs. Such methods have revealed a previously unknown structural complexity 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 functional analysis of PGs in human pathophysiology.

蛋白聚糖 (PGs) 是一类碳水化合物修饰的蛋白质，基本上存在于迄今为止研究的所有后生动物中。PGs 由附着在各种核心蛋白上的糖胺聚糖 (GAG) 链组成，对胚胎发生和正常体内平衡很重要。PG 通过其 GAG 链发挥其许多功能，了解 GAG-配体相互作用的细节一直是 PG 研究的重要组成部分。尽管 PGs 也与许多疾病有关，但临床上使用的 GAG 相关药物的数量仍然非常有限，这表明缺乏详细的结构功能了解。传统上，PG 的结构分析是通过首先将 GAG 链与核心蛋白分离，然后分别分析这两种成分来获得的。虽然这种策略极大地促进了分析，它排除了特定于站点的信息，并在数据解释上引入了“GAG”或“核心蛋白”观点。最近引入了质谱 (MS) 糖蛋白组学方法，可提供有关 PG 的特定位点信息。这些方法揭示了 GAG 连锁区域以前未知的结构复杂性，并导致在人类和模式生物中鉴定出几种新的 CSPG 和 HSPG，从而扩大了我们对 PG 复杂性的看法。鉴于这些发现，我们在这里讨论使用这种基于 MS 的技术与各种功能测定相结合是否也可用于扩展我们对 PG 的功能理解。我们还总结了迄今为止已知的所有人类 PG 的位点特异性信息，为未来研究位点特异性提供了理论框架。PGs在人类病理生理学中的功能分析。