Excavating proteoglycan structure-function relationships: modern approaches to capture the interactions of ancient biomolecules

Abstract

Proteoglycans are now well regarded as key facilitators of cell biology. While a majority of their interactions and functions are attributed to the decorating glycosaminoglycan chains, there is a growing appreciation for the roles of the proteoglycan core protein and for considering proteoglycans as replete protein-glycan conjugates. This appreciation, seeded by early work in proteoglycan biology, is now being advanced and exalted by modern approaches in chemical glycobiology. In this review, we discuss up-and-coming methods to unearth the fine-scale architecture of proteoglycans that modulate their functions and interactions. Crucial to these efforts is the production of chemically defined materials, including semi-synthetic proteoglycans and the in situ capture of interacting proteins. Together, the integration of chemical biology approaches promises to expedite the dissection of the structural heterogeneity of proteoglycans and deliver refined insight into their functions.

B3GALT6 promotes dormant breast cancer cell survival and recurrence by enabling heparan sulfate-mediated FGF signaling

“…Although our study is focused on the glycan component of proteoglycans, the core protein may also play an important role beyond serving as a scaffold for the attachment of GAGs. Indeed, sequences within the core protein can influence the stoichiometry 73 and sulfation pattern of GAG chains 72 , with important biological consequences 74 . The heparan sulfate proteoglycan family orchestrates diverse physiological functions 26 and includes transmembrane syndecans (SDC1-4), 6 glycophosphatidylinositol (GPI)-anchored glypicans (GPC1-6), as well as secreted perlecan, agrin, and collagen XVIII that are deposited in the extracellular matrix 25 .…”

Global impact of proteoglycan science on human diseases

“… 21 The recently updated GAG interactome contains about four times more GAG-binding proteins 2 than the originally established GAG interactome, 22 with a marked increase in the number of DS and HS/heparin-binding proteins. 2 Moreover, advances in structural data related to GAG biosynthesis, 23 novel chemical and biochemical tools for studying GAG sequencing, 24 and chemical glycobiology including the generation of semi-synthetic proteoglycans 25 have allowed the dissection of the structural heterogeneity and have ultimately provided powerful insights into proteoglycan functions. Surely, the exploration of the GAG interaction networks could be used for therapeutic purposes especially in the design of specific inhibitors targeting specific GAG/protein interactions.…”