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The 3- O -sulfation of heparan sulfate modulates protein binding and lyase degradation.

The 3- O -sulfation of heparan sulfate modulates protein binding and lyase degradation.

Authors :
Chopra P
Joshi A
Wu J
Lu W
Yadavalli T
Wolfert MA
Shukla D
Zaia J
Boons GJ
Source :
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Jan 19; Vol. 118 (3).
Publication Year :
2021

Abstract

Humans express seven heparan sulfate (HS) 3- O -sulfotransferases that differ in substrate specificity and tissue expression. Although genetic studies have indicated that 3- O -sulfated HS modulates many biological processes, ligand requirements for proteins engaging with HS modified by 3- O -sulfate (3-OS) have been difficult to determine. In particular, the context in which the 3-OS group needs to be presented for binding is largely unknown. We describe herein a modular synthetic approach that can provide structurally diverse HS oligosaccharides with and without 3-OS. The methodology was employed to prepare 27 hexasaccharides that were printed as a glycan microarray to examine ligand requirements of a wide range of HS-binding proteins. The binding selectivity of antithrombin-III (AT-III) compared well with anti-Factor Xa activity supporting robustness of the array technology. Many of the other examined HS-binding proteins required an IdoA2S-GlcNS3S6S sequon for binding but exhibited variable dependence for the 2-OS and 6-OS moieties, and a GlcA or IdoA2S residue neighboring the central GlcNS3S. The HS oligosaccharides were also examined as inhibitors of cell entry by herpes simplex virus type 1, which, surprisingly, showed a lack of dependence of 3-OS, indicating that, instead of glycoprotein D (gD), they competitively bind to gB and gC. The compounds were also used to examine substrate specificities of heparin lyases, which are enzymes used for depolymerization of HS/heparin for sequence determination and production of therapeutic heparins. It was found that cleavage by lyase II is influenced by 3-OS, while digestion by lyase I is only affected by 2-OS. Lyase III exhibited sensitivity to both 3-OS and 2-OS.<br />Competing Interests: The authors declare no competing interest.

Details

Language :
English
ISSN :
1091-6490
Volume :
118
Issue :
3
Database :
MEDLINE
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
33441484
Full Text :
https://doi.org/10.1073/pnas.2012935118