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Peptide Probes Reveal a Hydrophobic Steric Ratchet in the Anthrax Toxin Protective Antigen Translocase.

Abstract
Anthrax toxin is a tripartite virulence factor produced by Bacillus anthracis during infection. Under acidic endosomal pH conditions, the toxin's protective antigen (PA) component forms a transmembrane channel in host cells. The PA channel then translocates its two enzyme components, lethal factor and edema factor, into the host cytosol under the proton motive force. Protein translocation under a proton motive force is catalyzed by a series of nonspecific polypeptide binding sites, called clamps. A 10-residue guest/host peptide model system, KKKKKXXSXX, was used to functionally probe polypeptide-clamp interactions within wild-type PA channels. The guest residues were Thr, Ala, Leu, Phe, Tyr, and Trp. In steady-state translocation experiments, the channel blocked most tightly with peptides that had increasing amounts of nonpolar surface area. Cooperative peptide binding was observed in the Trp-containing peptide sequence but not the other tested sequences. Trp substitutions into a flexible, uncharged linker between the lethal factor amino-terminal domain and diphtheria toxin A chain expedited translocation. Therefore, peptide-clamp sites in translocase channels can sense large steric features (like tryptophan) in peptides, and while these steric interactions may make a peptide translocate poorly, in the context of folded domains, they can make the protein translocate more rapidly presumably via a hydrophobic steric ratchet mechanism.
AuthorsJennifer M Colby, Bryan A Krantz
JournalJournal of molecular biology (J Mol Biol) Vol. 427 Issue 22 Pg. 3598-3606 (Nov 06 2015) ISSN: 1089-8638 [Electronic] Netherlands
PMID26363343 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
Chemical References
  • Anthrax Vaccines
  • Antigens, Bacterial
  • Bacterial Toxins
  • Peptide Fragments
  • anthrax toxin
Topics
  • Anthrax Vaccines (chemistry, metabolism)
  • Antigens, Bacterial (chemistry, metabolism)
  • Bacillus anthracis (enzymology)
  • Bacterial Toxins (chemistry, metabolism)
  • Binding Sites
  • Cell Membrane (metabolism)
  • Electrophysiology
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Peptide Fragments (chemistry, metabolism)
  • Protein Transport

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