Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 25, Pages 10447-10452Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0700046104
Keywords
channels; chaperones; protein translocation; synaptic exocytosis
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Funding
- NIGMS NIH HHS [T32 GM08326, T32 GM008326] Funding Source: Medline
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The dynamics of Clostridium botulinum neurotoxins (BoNTs) protein-translocation across membranes was investigated by using a single molecule assay with millisecond resolution on excised patches of neuronal cells. Translocation of BoNT/A light chain (LC) by heavy chain (HC) was observed in real time as an increase of channel conductance: the HC channel is occluded by the LC during transit, then unoccluded after completion of translocation and release of LC-cargo. We identified an entirely unknown succession of intermediate conductance stages during LC translocation. For the single-chain BoNT/E, by contrast to the di-chain BoNT/A, we demonstrate that productive translocation requires proteolysis of the LC cargo from the HC chaperone. We propose a model for the set of protein-protein interactions between translocase and cargo at each step of translocation that supports the notion of an interdependent, tight interplay between the HC chaperone and the LC cargo preventing LC aggregation and dictating the outcome of translocation: productive passage of cargo or abortive channel occlusion by cargo.
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