Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 120, Issue 47, Pages 12064-12078Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.6b09400
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Funding
- Government of India, Department of Atomic Energy
- Government of India, Department of Science and Technology - Ramanujan Fellowship [SR/S2/RJN-63/2009]
- Department of Science and Technology (DST), Government of India
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Escherichia coli cytolysin A (ClyA) is an alpha-helical pore-forming toxin (PFT) which lyses target cells by forming membrane permeabilizing pores. The rate-determining step of this process is the conversion of the soluble ClyA monomer into a membrane inserted protomer. We elucidate the mechanism of this conformational transition using molecular dynamics simulations of coarse-grained models of ClyA and a membrane. We find that a membrane is necessary for the conformational conversion because membrane-protein interactions counteract the loss of the many-intraprotein hydrophobic interactions that stabilize the membrane-inserting segments in the ClyA monomer. Of the two membrane-inserting segments, the flexible and highly hydrophobic beta-tongue inserts first while the insertion of helix alpha A1 is membrane assisted. We conclude that the beta-tongue is designed to behave as a quick-response membrane sensor, while helix alpha A1 improves target selectivity for cholesterol-containing cell membranes by acting as a fidelity check.
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