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Structural basis for tuning activity and membrane specificity of bacterial cytolysins

Nita R. Shah, Tomas B. Voisin, Edward S. Parsons, Courtney M. Boyd, View ORCID ProfileBart W. Hoogenboom, View ORCID ProfileDoryen Bubeck
doi: https://doi.org/10.1101/2020.06.16.154724
Nita R. Shah
1Department of Life Sciences, Sir Ernst Chain Building, Imperial College London, London, SW7 2AZ, UK
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Tomas B. Voisin
1Department of Life Sciences, Sir Ernst Chain Building, Imperial College London, London, SW7 2AZ, UK
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Edward S. Parsons
2London Centre for Nanotechnology, University College London, London, WC1H 0AH, UK
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Courtney M. Boyd
1Department of Life Sciences, Sir Ernst Chain Building, Imperial College London, London, SW7 2AZ, UK
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Bart W. Hoogenboom
2London Centre for Nanotechnology, University College London, London, WC1H 0AH, UK
3Department of Physics and Astronomy, University College London, Gower Street, London, WC1E 6BT, UK
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  • ORCID record for Bart W. Hoogenboom
Doryen Bubeck
1Department of Life Sciences, Sir Ernst Chain Building, Imperial College London, London, SW7 2AZ, UK
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  • For correspondence: d.bubeck@imperial.ac.uk
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ABSTRACT

Cholesterol-dependent cytolysins (CDCs) form protein nanopores to lyse cells. 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 will facilitate engineering the target-cell specificity of pore-forming proteins.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted June 17, 2020.
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Structural basis for tuning activity and membrane specificity of bacterial cytolysins
Nita R. Shah, Tomas B. Voisin, Edward S. Parsons, Courtney M. Boyd, Bart W. Hoogenboom, Doryen Bubeck
bioRxiv 2020.06.16.154724; doi: https://doi.org/10.1101/2020.06.16.154724
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Structural basis for tuning activity and membrane specificity of bacterial cytolysins
Nita R. Shah, Tomas B. Voisin, Edward S. Parsons, Courtney M. Boyd, Bart W. Hoogenboom, Doryen Bubeck
bioRxiv 2020.06.16.154724; doi: https://doi.org/10.1101/2020.06.16.154724

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