title: Capturing the Membrane-Triggered Conformational Transition of an α-Helical Pore-Forming Toxin.
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.
authors: Simons Centre for the Study of Living Machines, National Centre for Biological Sciences, Tata Institute of Fundamental Research , Bengaluru 560065, India.
authors: V V Hemanth
authors: VV
authors: Giri Rao
authors: Department of Chemical Engineering, Indian Institute of Science , Bengaluru 560012, India.
authors: Rajat
authors: R
authors: Desikan
authors: Department of Chemical Engineering, Indian Institute of Science , Bengaluru 560012, India.|Centre for Biosystems Science and Engineering, Indian Institute of Science , Bengaluru 560012, India.
authors: K Ganapathy
authors: KG
authors: Ayappa
authors: Simons Centre for the Study of Living Machines, National Centre for Biological Sciences, Tata Institute of Fundamental Research , Bengaluru 560065, India.
authors: Shachi
authors: S
authors: Gosavi
mesh_terms: D001665:Binding Sites; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism; D004926:Escherichia coli / Q000737:chemistry* / Q000378:metabolism / Q000472:pathogenicity; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000378:metabolism; D006460:Hemolysin Proteins / Q000737:chemistry* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D052899:Pore Forming Cytotoxic Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D012995:Solubility; D013816:Thermodynamics
chemical_list: D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; D052899:Pore Forming Cytotoxic Proteins; C119944:hlyE protein, E coli