Dissecting structure-function of 3-O-sulfated heparin and engineered heparan sulfates
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Dokumenter
- Fulltext
Forlagets udgivne version, 2,11 MB, PDF-dokument
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.
Originalsprog | Engelsk |
---|---|
Artikelnummer | eabl6026 |
Tidsskrift | Science Advances |
Vol/bind | 7 |
Udgave nummer | 52 |
ISSN | 2375-2548 |
DOI | |
Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
This work was funded by The Carlsberg Foundation CF20-0412 (R.L.M.); The Lundbeck Foundation, R223-2016-563 (H.C.); The Danish National Research Foundation DNRF107 (H.C.); The European Commission, GlycoImaging H2020-MSCA-ITN-721297 (H.C. and R.K.); NIH, P41GM103390 and HLBI R01HL151617 (G.-J.B.); The Sir Henry Dale Fellowship, Welcome Trust/Royal Society 218570/Z/19/Z (D.P.D.); The National Science Foundation, RAPID 2031989 (J.E.T.); NIH, HL131474 (J.D.E.); and The Deutsche Forschungsgemeinschaft, German Research Foundation SFB 1340 (K.P.).
Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved.
Antal downloads er baseret på statistik fra Google Scholar og www.ku.dk
ID: 289392736