N-glycan microheterogeneity regulates interactions of plasma proteins

Di Wu, Weston B Struwe, David J Harvey, Michael A J Ferguson, Carol V Robinson

Research output: Contribution to journalArticlepeer-review

85 Citations (Scopus)
135 Downloads (Pure)


Altered glycosylation patterns of plasma proteins are associated with autoimmune disorders and pathogenesis of various cancers. Elucidating glycoprotein microheterogeneity and relating subtle changes in the glycan structural repertoire to changes in protein-protein, or protein-small molecule interactions, remains a significant challenge in glycobiology. Here, we apply mass spectrometry-based approaches to elucidate the global and site-specific microheterogeneity of two plasma proteins: α1-acid glycoprotein (AGP) and haptoglobin (Hp). We then determine the dissociation constants of the anticoagulant warfarin to different AGP glycoforms and reveal how subtle N-glycan differences, namely, increased antennae branching and terminal fucosylation, reduce drug-binding affinity. Conversely, similar analysis of the haptoglobin-hemoglobin (Hp-Hb) complex reveals the contrary effects of fucosylation and N-glycan branching on Hp-Hb interactions. Taken together, our results not only elucidate how glycoprotein microheterogeneity regulates protein-drug/protein interactions but also inform the pharmacokinetics of plasma proteins, many of which are drug targets, and whose glycosylation status changes in various disease states.

Original languageEnglish
Article number 201807439
Pages (from-to)8763-8768
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number35
Early online date15 Aug 2018
Publication statusPublished - 28 Aug 2018


  • glycoprotein
  • mass spectrometry
  • protein interactions
  • Glycoprotein
  • Mass spectrometry
  • Protein interactions
  • Glucans/chemistry
  • Models, Chemical
  • Humans
  • Haptoglobins/chemistry
  • Orosomucoid/chemistry
  • Warfarin/chemistry

ASJC Scopus subject areas

  • General


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