Journal article

The Structural Basis for a Transition State That Regulates Pore Formation in a Bacterial Toxin

Kristin R Wade, Sara L Lawrence, Allison J Farrand, Eileen M Hotze, Michael J Kuiper, Michael A Gorman, Michelle P Christie, Santosh Panjikar, Craig J Morton, Michael W Parker, Rodney K Tweten



The cholesterol-dependent cytolysin (CDC) genes are present in bacterial species that span terrestrial, vertebrate, and invertebrate niches, which suggests that they have evolved to function under widely different environmental conditions. Using a combination of biophysical and crystallographic approaches, we reveal that the relative stability of an intramolecular interface in the archetype CDC perfringolysin O (PFO) plays a central role in regulating its pore-forming properties. The disruption of this interface allows the formation of the membrane spanning β-barrel pore in all CDCs. We show here that the relative strength of the stabilizing forces at this interface directly impacts the ener..

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Awarded by National Institutes of Health (NIAID)

Awarded by Australian Research Council

Awarded by Victorian Life Sciences Computation Initiative

Funding Acknowledgements

This work was supported by the National Institutes of Health (NIAID) (R37-AI037657 to R.K.T.). An Australian Research Council Discovery Grant (DP160101874) to M.W.P. supported the structural studies. MD simulations were supported by a grant from the Victorian Life Sciences Computation Initiative (VR0021) on its Peak Computing Facility (University of Melbourne), an initiative of the Victorian Government and by resources provided by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. Funding from the Victorian Government Operational Infrastructure Support Scheme to St Vincent's Institute is acknowledged. M.W.P. is a National Health and Medical Research Council of Australia Research Fellow.