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Disentangling the roles of cholesterol and CD59 in intermedilysin pore formation

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Title: Disentangling the roles of cholesterol and CD59 in intermedilysin pore formation
Authors: Boyd, C
Parsons, ES
Smith, RAG
Seddon, JM
Ces, O
Bubeck, D
Item Type: Journal Article
Abstract: The plasma membrane provides an essential barrier, shielding a cell from the pressures of its external environment. Pore-forming proteins, deployed by both hosts and pathogens alike, breach this barrier to lyse target cells. Intermedilysin is a cholesterol-dependent cytolysin that requires the human immune receptor CD59, in addition to cholesterol, to form giant β-barrel pores in host membranes. Here we integrate biochemical assays with electron microscopy and atomic force microscopy to distinguish the roles of these two receptors in mediating structural transitions of pore formation. CD59 is required for the specific coordination of intermedilysin (ILY) monomers and for triggering collapse of an oligomeric prepore. Movement of Domain 2 with respect to Domain 3 of ILY is essential for forming a late prepore intermediate that releases CD59, while the role of cholesterol may be limited to insertion of the transmembrane segments. Together these data define a structural timeline for ILY pore formation and suggest a mechanism that is relevant to understanding other pore-forming toxins that also require CD59.
Issue Date: 2-Dec-2016
Date of Acceptance: 8-Nov-2016
URI: http://hdl.handle.net/10044/1/42380
DOI: https://dx.doi.org/10.1038/srep38446
ISSN: 2045-2322
Publisher: Nature Publishing Group
Journal / Book Title: Scientific Reports
Volume: 6
Copyright Statement: © The Author(s) 2016. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Sponsor/Funder: Engineering & Physical Science Research Council (EPSRC)
Cancer Research UK
Funder's Grant Number: EP/J017566/1
A16099
Publication Status: Published
Article Number: 38446
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
Faculty of Natural Sciences



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