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Structural basis for tuning activity and membrane specificity of bacterial cytolysins

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Title: Structural basis for tuning activity and membrane specificity of bacterial cytolysins
Authors: Shah, NR
Voisin, TB
Parsons, ES
Boyd, CM
Hoogenboom, BW
Bubeck, D
Item Type: Journal Article
Abstract: Cholesterol-dependent cytolysins (CDCs) are pore-forming proteins that serve as major virulence factors for pathogenic bacteria. They target eukaryotic cells using different mechanisms, but all require the presence of cholesterol to pierce lipid bilayers. How CDCs use cholesterol to selectively lyse cells is essential for understanding virulence strategies of several pathogenic bacteria, and for repurposing CDCs to kill new cellular targets. Here we address that question by trapping an early state of pore formation for the CDC intermedilysin, bound to the human immune receptor CD59 in a nanodisc model membrane. Our cryo electron microscopy map reveals structural transitions required for oligomerization, which include the lateral movement of a key amphipathic helix. We demonstrate that the charge of this helix is crucial for tuning lytic activity of CDCs. Furthermore, we discover modifications that overcome the requirement of cholesterol for membrane rupture, which may facilitate engineering the target-cell specificity of pore-forming proteins.
Issue Date: 16-Nov-2020
Date of Acceptance: 5-Oct-2020
URI: http://hdl.handle.net/10044/1/84679
DOI: 10.1038/s41467-020-19482-6
ISSN: 2041-1723
Publisher: Nature Research
Journal / Book Title: Nature Communications
Volume: 11
Copyright Statement: © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Cancer Research UK
Wellcome Trust
Funder's Grant Number: 16099
212938/Z/18/Z
Keywords: CD59 Antigens
Cell Membrane
Cryoelectron Microscopy
Cytotoxins
Humans
Models, Biological
Models, Molecular
Mutation
Protein Structure, Secondary
Structure-Activity Relationship
Cell Membrane
Humans
Cytotoxins
Cryoelectron Microscopy
Protein Structure, Secondary
Structure-Activity Relationship
Mutation
Models, Biological
Models, Molecular
CD59 Antigens
Publication Status: Published
Article Number: ARTN 5818
Appears in Collections:Faculty of Natural Sciences



This item is licensed under a Creative Commons License Creative Commons