Chemical editing of proteoglycan architecture

Proteoglycans are heterogeneous macromolecular glycoconjugates that orchestrate many important cellular processes. While much attention has focused on the poly-sulfated glycosaminoglycan chains that decorate proteoglycans, other important elements of their architecture, such as core proteins and membrane localization, have garnered less emphasis. Hence, comprehensive structure-function relationships that consider the replete proteoglycan architecture as glycoconjugates are limited. Here we present an extensive approach to study proteoglycan structure and biology by fabricating defined semisynthetic modular proteoglycans that can be tailored for cell surface display. The expression of proteoglycan core proteins with unnatural amino acids permits bioorthogonal click chemistry with functionalized glycosaminoglycans for methodical dissection of the parameters required for optimal binding and function of various proteoglycan-binding proteins. We demonstrate that these sophisticated materials can recapitulate the functions of native proteoglycan ectodomains in mouse embryonic stem cell differentiation and cancer cell spreading while permitting the analysis of the contributing architectural elements toward function.

Automated summary

Proteoglycans are important glycoconjugates that play a role in many cellular processes. However, the study of their structure and function has mainly focused on the glycosaminoglycan chains, overlooking other important elements such as core proteins and membrane localization. In this study, we present a comprehensive approach to investigate proteoglycan structure and biology by creating tailored semisynthetic modular proteoglycans that can be displayed on the cell surface. By using proteoglycan core proteins with unnatural amino acids, we were able to systematically study the binding and function of various proteoglycan-binding proteins.