Interactions of pleiotrophin with a structurally defined heparin hexasaccharide

Eathen O. Ryan, Zhoumai Jiang, Hoa Nguyen, Xu Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Pleiotrophin (PTN) is a potent cytokine that plays an important role in neural generation, angiogenesis, inflammation, and cancers. Its interactions with the polysaccharide glycosaminoglycan (GAG) are crucial to PTN’s biological activities. In this study, we investigated the interaction of selectively protonated PTN with the heparin hexasaccharide ∆UA2S-(GlcNS6S-IdoA2S)2-GlcNS6S using solution NMR. The use of a structurally defined oligosaccharide and selectively protonated PTN enabled us to obtain intermolecular contacts using unfiltered NOESY experiments, significantly increasing the amount of high-resolution structural information obtainable. Our data showed that PTN’s arginines, lysines, and tryptophans in the two structured domains have strong interactions with the 2-O-sulfated uronate protons in the heparin hexasaccharide. Consistent with the NMR data is the observation that 2-O-desulfation and N-desulfation/N-acetylation significantly decreased heparin hexasaccharides’ affinity for PTN, while 6-O-desulfation only modestly affected the interactions with PTN. These results allowed us to hypothesize that PTN has a preference for sulfate clusters centered on the GlcNS6S-IdoA2S disaccharide. Using these data and the fact that PTN domains mostly bind heparin hexasaccharides independently, models of the PTN-heparin complex were constructed.

Original languageEnglish (US)
Article number50
JournalBiomolecules
Volume12
Issue number1
DOIs
StatePublished - Jan 2022
Externally publishedYes

Keywords

  • Cytokine
  • GAG-binding protein
  • Glycosaminoglycan
  • Heparin
  • NMR
  • Pleiotrophin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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