Capturing the Membrane-Triggered Conformational Transition of an α-Helical Pore-Forming Toxin

J Phys Chem B. 2016 Dec 1;120(47):12064-12078. doi: 10.1021/acs.jpcb.6b09400. Epub 2016 Nov 17.

Abstract

Escherichia coli cytolysin A (ClyA) is an α-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 β-tongue inserts first while the insertion of helix αA1 is membrane assisted. We conclude that the β-tongue is designed to behave as a quick-response membrane sensor, while helix αA1 improves target selectivity for cholesterol-containing cell membranes by acting as a fidelity check.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Membrane / chemistry*
  • Cell Membrane / metabolism
  • Escherichia coli / chemistry*
  • Escherichia coli / metabolism
  • Escherichia coli / pathogenicity
  • Escherichia coli Proteins / chemistry*
  • Escherichia coli Proteins / metabolism
  • Hemolysin Proteins / chemistry*
  • Hemolysin Proteins / metabolism
  • Hydrophobic and Hydrophilic Interactions
  • Kinetics
  • Molecular Dynamics Simulation
  • Pore Forming Cytotoxic Proteins / chemistry*
  • Pore Forming Cytotoxic Proteins / metabolism
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Solubility
  • Thermodynamics

Substances

  • Escherichia coli Proteins
  • Hemolysin Proteins
  • Pore Forming Cytotoxic Proteins
  • hlyE protein, E coli