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

Autor: 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, Hansen, Lars, Esko, Jeffrey D, Pagel, Kevin, Dyer, Douglas P, Turnbull, Jeremy E, Clausen, Henrik, Boons, Geert-Jan, Miller, Rebecca L, Afd Chemical Biology and Drug Discovery, Sub Chemical Biology and Drug Discovery, Chemical Biology and Drug Discovery
Přispěvatelé: Afd Chemical Biology and Drug Discovery, Sub Chemical Biology and Drug Discovery, Chemical Biology and Drug Discovery
Rok vydání: 2021
Předmět:
Zdroj: Science Advances
Karlsson, R, Chopra, P, Joshi, A, Yang, Z, Vakhrushev, S Y, Clausen, T M, Painter, C D, Szekeres, G P, Chen, Y H, Sandoval, D R, Hansen, L, Esko, J D, Pagel, K, Dyer, D P, Turnbull, J E, Clausen, H, Boons, G J & Miller, R L 2021, ' Dissecting structure-function of 3-O-sulfated heparin and engineered heparan sulfates ', Science Advances, vol. 7, no. 52, eabl6026 . https://doi.org/10.1126/sciadv.abl6026
Science advances, 7(52), 1. American Association for the Advancement of Science
Karlsson, R, Chopra, P, Joshi, A, Yang, Z, Vakhrushev, S Y, Clausen, T M, Painter, C D, Szekeres, G P, Chen, Y-H, Sandoval, D R, Hansen, L, Esko, J D, Pagel, K, Dyer, D P, Turnbull, J E, Clausen, H, Boons, G-J & Miller, R L 2021, ' Dissecting structure-function of 3-O-sulfated heparin and engineered heparan sulfates ', Science Advances, vol. 7, no. 52, eabl6026, pp. eabl6026 . https://doi.org/10.1126/sciadv.abl6026
Science advances, vol 7, iss 52
ISSN: 2375-2548
DOI: 10.1126/sciadv.abl6026
Popis: Description
This study provides proof of concept for cell-based heparin without heparin-induced thrombocytopenia side effects.
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-O-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-O-sulfate structure-function and demonstrate proof of concept for tailored cell-based synthesis of next-generation heparins.
Databáze: OpenAIRE
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