Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/126437
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Type: | Journal article |
Title: | All major cholesterol-dependent cytolysins use glycans as cellular receptors |
Author: | Shewell, L.K. Day, C.J. Jen, F.E.-C. Haselhorst, T. Atack, J.M. Reijneveld, J.F. Everest-Dass, A. James, D.B.A. Boguslawski, K.M. Brouwer, S. Gillen, C.M. Luo, Z. Kobe, B. Nizet, V. von Itzstein, M. Walker, M.J. Paton, A.W. Paton, J.C. Torres, V.J. Jennings, M.P. |
Citation: | Science Advances, 2020; 6(21):eaaz4926-1-eaaz4926-14 |
Publisher: | American Association for the Advancement of Science |
Issue Date: | 2020 |
ISSN: | 2375-2548 2375-2548 |
Statement of Responsibility: | Lucy K. Shewell, Christopher J. Day, Freda E.-C. Jen, Thomas Haselhorst, John M. Atack, Josephine F. Reijneveld, Arun Everest-Dass, David B. A. James, Kristina M. Boguslawski, Stephan Brouwer, Christine M. Gillen, Zhenyao Luo, Bostjan Kobe, Victor Nizet, Mark von Itzstein, Mark J. Walker, Adrienne W. Paton, James C. Paton, Victor J. Torres, Michael P. Jennings |
Abstract: | Cholesterol-dependent cytolysins (CDCs) form pores in cholesterol-rich membranes, but cholesterol alone is insufficient to explain their cell and host tropism. Here, we show that all eight major CDCs have high-affinity lectin activity that identifies glycans as candidate cellular receptors. Streptolysin O, vaginolysin, and perfringolysin O bind multiple glycans, while pneumolysin, lectinolysin, and listeriolysin O recognize a single glycan class. Addition of exogenous carbohydrate receptors for each CDC inhibits toxin activity. We present a structure for suilysin domain 4 in complex with two distinct glycan receptors, P1 antigen and αGal/Galili. We report a wide range of binding affinities for cholesterol and for the cholesterol analog pregnenolone sulfate and show that CDCs bind glycans and cholesterol independently. Intermedilysin binds to the sialyl-TF O-glycan on its erythrocyte receptor, CD59. Removing sialyl-TF from CD59 reduces intermedilysin binding. Glycan-lectin interactions underpin the cellular tropism of CDCs and provide molecular targets to block their cytotoxic activity. |
Keywords: | Cholesterol Polysaccharides Lectins Receptors, Cell Surface Cytotoxins |
Rights: | Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
DOI: | 10.1126/sciadv.aaz4926 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1071659 http://purl.org/au-research/grants/nhmrc/1138466 http://purl.org/au-research/grants/nhmrc/1102621 http://purl.org/au-research/grants/nhmrc/1110971 http://purl.org/au-research/grants/arc/FT120100419 http://purl.org/au-research/grants/arc/DP170104692 http://purl.org/au-research/grants/arc/FL180100109 |
Published version: | http://dx.doi.org/10.1126/sciadv.aaz4926 |
Appears in Collections: | Aurora harvest 8 Molecular and Biomedical Science publications |
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hdl_126437.pdf | Published version | 748.56 kB | Adobe PDF | View/Open |
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