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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.
- 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
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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.
- Subjects :
- Acetylglucosamine chemistry
Acetylglucosamine metabolism
Antithrombin III chemistry
Antithrombin III genetics
Antithrombin III metabolism
Binding Sites
Binding, Competitive
Carbohydrate Sequence
Cell Line
Cornea cytology
Cornea metabolism
Epithelial Cells pathology
Epithelial Cells virology
Factor Xa chemistry
Factor Xa genetics
Factor Xa metabolism
Factor Xa Inhibitors chemistry
Factor Xa Inhibitors metabolism
Gene Expression
Glucuronic Acid chemistry
Glucuronic Acid metabolism
Heparin Lyase chemistry
Heparin Lyase genetics
Heparitin Sulfate chemistry
Herpesvirus 1, Human growth & development
Host-Pathogen Interactions genetics
Humans
Isoenzymes chemistry
Isoenzymes genetics
Isoenzymes metabolism
Microarray Analysis
Protein Binding
Proteolysis
Small Molecule Libraries
Substrate Specificity
Sulfates chemistry
Sulfotransferases chemistry
Sulfotransferases genetics
Viral Envelope Proteins chemistry
Viral Envelope Proteins genetics
Viral Envelope Proteins metabolism
Epithelial Cells metabolism
Heparin Lyase metabolism
Heparitin Sulfate metabolism
Herpesvirus 1, Human metabolism
Sulfates metabolism
Sulfotransferases metabolism
Subjects
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