Dissecting structure-function of 3-O-sulfated heparin and engineered heparan sulfates



Karlsson, Richard, Chopra, Pradeep, Joshi, Apoorva, Yang, Zhang, Vakhrushev, Sergey Y, Clausen, Thomas Mandel, Painter, Chelsea D, Szekeres, Gergo P, Chen, Yen-Hsi, Sandoval, Daniel R
et al (show 8 more authors) (2021) Dissecting structure-function of 3-O-sulfated heparin and engineered heparan sulfates. SCIENCE ADVANCES, 7 (52). eabl6026-.

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Abstract

Heparan sulfate (HS) polysaccharides are master regulators of diverse biological processes via sulfated motifs that can recruit specific proteins. 3-O-sulfation of HS/heparin is crucial for anticoagulant activity, but despite emerging evidence for roles in many other functions, a lack of tools for deciphering structure-function relationships has hampered advances. Here, we describe an approach integrating synthesis of 3-O-sulfated standards, comprehensive HS disaccharide profiling, and cell engineering to address this deficiency. Its application revealed previously unseen differences in 3-O-sulfated profiles of clinical heparins and 3-<i>O</i>-sulfotransferase (HS3ST)–specific variations in cell surface HS profiles. The latter correlated with functional differences in anticoagulant activity and binding to platelet factor 4 (PF4), which underlies heparin-induced thrombocytopenia, a known side effect of heparin. Unexpectedly, cells expressing the HS3ST4 isoenzyme generated HS with potent anticoagulant activity but weak PF4 binding. The data provide new insights into 3-<i>O</i>-sulfate structure-function and demonstrate proof of concept for tailored cell-based synthesis of next-generation heparins.

Item Type: Article
Uncontrolled Keywords: Hematology
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 18 May 2022 09:19
Last Modified: 15 Mar 2024 10:47
DOI: 10.1126/sciadv.abl6026
Open Access URL: https://doi.org/10.1126/sciadv.abl6026
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3155028