Characterizing Heparin Tetrasaccharides Binding to Amyloid-Beta Peptide

Xiang Zhou; Yuanyuan Wang; Wei Zheng; Guangxiu Deng; Fuyi Wang; Lan Jin

doi:10.3389/fmolb.2022.824146

Characterizing Heparin Tetrasaccharides Binding to Amyloid-Beta Peptide

Front Mol Biosci. 2022 Feb 23:9:824146. doi: 10.3389/fmolb.2022.824146. eCollection 2022.

Authors

Xiang Zhou¹, Yuanyuan Wang², Wei Zheng², Guangxiu Deng¹, Fuyi Wang³, Lan Jin¹

Affiliations

¹ National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Qingdao, China.
² Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems Institute of Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China.
³ College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.

Abstract

The aggregation of β-amyloid peptide (Aβ) is one potential cause for Alzheimer's disease (AD). Heparin can either promote or inhibit Aβ aggregation. The sulfation pattern and chain size determine its binding affinity and its role. Using 2D-NMR analysis and molecular modelling, the binding motif of heparin oligoaccharides to Aβ was determined to be HexA-GlcNS-IdoA2S-GlcNS6S. Iduronic acid epimerization and 6-O-sulfation are key factors for the binding affinity, while 3-O-sulfation of Arixtra (heparin pentasaccharide) is not involved in the binding to Aβ. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) was used to study the glycosaminoglycan (GAG)-peptide complex and identified V12HHQKL17 as the binding site of GAG at Aβ. Furthermore, an MTT assay was applied to evaluate the anti-Aβ fibril formation function of heparin tetrasaccharide, and indicated that the heparin tetrasaccharide with the defined sequence represents a promising inhibitor of Aβ aggregation.

Keywords: NMR; heparin; hydrogen/deuterium exchange mass spectrometry; interaction; β-amyloid peptide.