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

Research output: Contribution to journal › Journal article › Research › peer-review

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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.; Hansen, Lars; Esko, Jeffrey D.; Pagel, Kevin; Dyer, Douglas P.; Turnbull, Jeremy E.; Clausen, Henrik; Boons, Geert Jan; Miller, Rebecca L.

In: Science Advances, Vol. 7, No. 52, eabl6026, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Karlsson, R, Chopra, P, Joshi, A, Yang, Z, Vakhrushev, SY, Clausen, TM, Painter, CD, Szekeres, GP, Chen, YH, Sandoval, DR, Hansen, L, Esko, JD, Pagel, K, Dyer, DP, Turnbull, JE, Clausen, H, Boons, GJ & Miller, RL 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

APA

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, 7(52), [eabl6026]. https://doi.org/10.1126/sciadv.abl6026

Vancouver

Karlsson R, Chopra P, Joshi A, Yang Z, Vakhrushev SY, Clausen TM et al. Dissecting structure-function of 3-O-sulfated heparin and engineered heparan sulfates. Science Advances. 2021;7(52). eabl6026. https://doi.org/10.1126/sciadv.abl6026

Author

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. / Dissecting structure-function of 3-O-sulfated heparin and engineered heparan sulfates. In: Science Advances. 2021 ; Vol. 7, No. 52.

Bibtex

@article{33141879595544a299855338d09122dd,

title = "Dissecting structure-function of 3-O-sulfated heparin and engineered heparan sulfates",

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-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. ",

author = "Richard Karlsson and Pradeep Chopra and Apoorva Joshi and Zhang Yang and Vakhrushev, {Sergey Y.} and Clausen, {Thomas Mandel} and Painter, {Chelsea D.} and Szekeres, {Gergo P.} and Chen, {Yen Hsi} and Sandoval, {Daniel R.} and Lars Hansen and Esko, {Jeffrey D.} and Kevin Pagel and Dyer, {Douglas P.} and Turnbull, {Jeremy E.} and Henrik Clausen and Boons, {Geert Jan} and Miller, {Rebecca L.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved.",

year = "2021",

doi = "10.1126/sciadv.abl6026",

language = "English",

volume = "7",

journal = "Science advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "52",

}

RIS

TY - JOUR

T1 - Dissecting structure-function of 3-O-sulfated heparin and engineered heparan sulfates

AU - Karlsson, Richard

AU - Chopra, Pradeep

AU - Joshi, Apoorva

AU - Yang, Zhang

AU - Vakhrushev, Sergey Y.

AU - Clausen, Thomas Mandel

AU - Painter, Chelsea D.

AU - Szekeres, Gergo P.

AU - Chen, Yen Hsi

AU - Sandoval, Daniel R.

AU - Hansen, Lars

AU - Esko, Jeffrey D.

AU - Pagel, Kevin

AU - Dyer, Douglas P.

AU - Turnbull, Jeremy E.

AU - Clausen, Henrik

AU - Boons, Geert Jan

AU - Miller, Rebecca L.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1126/sciadv.abl6026

DO - 10.1126/sciadv.abl6026

M3 - Journal article

C2 - 34936441

AN - SCOPUS:85122026279

VL - 7

JO - Science advances

JF - Science advances

SN - 2375-2548

IS - 52

M1 - eabl6026

ER -

ID: 289392736

Forskning