Open AccessChemical editing of proteoglycan architecture
Author(s) -
Timothy R. O’Leary,
Meg Critcher,
Tesia N. Stephenson,
Xueyi Yang,
Abdullah A. Hassan,
Noah M. Bartfield,
Richard L. Hawkins,
Mia L. Huang
Publication year - 2022
Publication title -
nature chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.412
H-Index - 216
eISSN - 1552-4469
pISSN - 1552-4450
DOI - 10.1038/s41589-022-01023-5
Subject(s) - proteoglycan , microbiology and biotechnology , function (biology) , embryonic stem cell , cell , chemistry , bioorthogonal chemistry , biology , biochemistry , computational biology , click chemistry , extracellular matrix , gene , combinatorial chemistry
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.