4.4 Article Proceedings Paper

Translocation of botulinum neurotoxin light chain protease by the heavy chain protein-conducting channel

Journal

TOXICON
Volume 54, Issue 5, Pages 565-569

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.toxicon.2008.11.018

Keywords

Chaperone; Channels; Protein translocation; Membranes; Neurotoxicity

Funding

  1. NIAID NIH HHS [U54 AI065359, AI065359, U54 AI065359-01] Funding Source: Medline

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Clostridial botulinum neurotoxins (BoNTs) inhibit synaptic exocytosis; intoxication requires the di-chain protein to undergo conformational changes in response to pH and redox gradients across the endosomal membrane with consequent formation of a protein-conducting channel by the heavy chain (HQ that translocates the light chain (LC) protease into the cytosol, colocalizing it with the substrate SNARE proteins. We investigate the dynamics of protein translocation across membranes using a sensitive single-molecule assay to track translocation events with millisecond resolution on lipid bilayers and on membrane patches of Neuro 2A cells. Translocation of BoNT/A LC by the HC is observed in real time as changes of channel conductance: the channel is occluded by the light chain during transit, and open after completion of translocation and release of cargo, acting intriguingly similar to the protein-conducting/translocating channels of the endoplasmic reticulum, mitochondria, and chloroplasts. Our findings support the notion of an interdependent, tight interplay between the HC transmembrane chaperone and the LC cargo that prevents LC aggregation and dictates the productive passage of cargo through the channel and completion of translocation. The protein-conducting channel of BoNT, a key element in the process of neurotoxicity, emerges therefore as a target for antidote discovery - a novel paradigm of paramount significance to health science and biodefense. (C) 2008 Elsevier Ltd. All rights reserved.

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