期刊
NATURE
卷 549, 期 7673, 页码 538-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature24015
关键词
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资金
- Austrian Science Fund [SFB F3402-B03, TRP308-N15, I1469-B16]
- IMBA
- Austrian Academy of Sciences
- ERC
- Era of Hope Innovator award
- Austrian Science Fund (FWF) [TRP 308] Funding Source: researchfish
- Austrian Science Fund (FWF) [TRP308] Funding Source: Austrian Science Fund (FWF)
Glycosylation, the covalent attachment of carbohydrate structures onto proteins, is the most abundant post-translational modification(1). Over 50% of human proteins are glycosylated, which alters their activities in diverse fundamental biological processes(2,3). Despite the importance of glycosylation in biology(4), the identification and functional validation of complex glycoproteins has remained largely unexplored. Here we develop a novel quantitative approach to identify intact glycopeptides from comparative proteomic data sets, allowing us not only to infer complex glycan structures but also to directly map them to sites within the associated proteins at the proteome scale. We apply this method to human and mouse embryonic stem cells to illuminate the stem cell glycoproteome. This analysis nearly doubles the number of experimentally confirmed glycoproteins, identifies previously unknown glycosylation sites and multiple glycosylated stemness factors, and uncovers evolutionarily conserved as well as species-specific glycoproteins in embryonic stem cells. The specificity of our method is confirmed using sister stem cells carrying repairable mutations in enzymes required for fucosylation, Fut9 and Slc35c1. Ablation of fucosylation confers resistance to the bioweapon ricin(5,6), and we discover proteins that carry a fucosylation-dependent sugar code for ricin toxicity. Mutations disrupting a subset of these proteins render cells ricin resistant, revealing new players that orchestrate ricin toxicity. Our comparative glycoproteomics platform, SugarQb, enables genome-wide insights into protein glycosylation and glycan modifications in complex biological systems.
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