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DOI	10.1073/PNAS.2012935118
	The 3-O-sulfation of heparan sulfate modulates protein binding and lyase degradation
	Chopra P.; Joshi A.; Wu J.; Lu W.; Yadavalli T.; Wolfert M.A.; Shukla D.; Zaia J.; Boons G.-J.
发表日期	2021
ISSN	00278424
卷号	118 期号:3
英文摘要	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 IdoA2SGlcNS3S6S 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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	3-O-sulfation; Anti-Factor Xa; Glycan microarray; Heparin lyases; Herpes simplex virus 1
语种	英语
scopus关键词	antithrombin III; blood clotting factor 10a; glycoprotein B; glycoprotein D; heparan sulfate; heparin; heparin lyase; heparin lyase I; heparin lyase II; heparin lyase III; lyase; protein C; unclassified drug; antiviral activity; Article; binding affinity; controlled study; depolymerization; drug design; drug synthesis; enzyme degradation; enzyme specificity; Human alphaherpesvirus 1; IC50; nonhuman; priority journal; protein binding; sulfation; virus entry
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/181012
作者单位	Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, United States; Department of Chemistry, University of Georgia, Athens, GA 30602, United States; Department of Biochemistry, Center for Biomedical Mass Spectrometry, Boston University of Medicine, Boston, MA 02118, United States; Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, United States; Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, 3584 CG, Netherlands; Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, United States
推荐引用方式 GB/T 7714	Chopra P.,Joshi A.,Wu J.,et al. The 3-O-sulfation of heparan sulfate modulates protein binding and lyase degradation[J],2021,118(3).
APA	Chopra P..,Joshi A..,Wu J..,Lu W..,Yadavalli T..,...&Boons G.-J..(2021).The 3-O-sulfation of heparan sulfate modulates protein binding and lyase degradation.Proceedings of the National Academy of Sciences of the United States of America,118(3).
MLA	Chopra P.,et al."The 3-O-sulfation of heparan sulfate modulates protein binding and lyase degradation".Proceedings of the National Academy of Sciences of the United States of America 118.3(2021).