Toxin studies using an integrated biophysical and structural biology approach.

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Clostridial neurotoxins, such as botulinum and tetanus, are generally thought to invade neural cells through a process of high affinity binding mediated by gangliosides, internalization via endosome formation, and subsequent membrane penetration of the catalytic domain activated by a pH drop in the endosome. This surface recognition and internalization process is still not well understood with regard to what specific membrane features the toxins target, the intermolecular interactions between bound toxins, and the molecular conformational changes that occur as a result of pH lowering. In an effort to elucidate the mechanism of tetanus toxin binding and permeation through the membrane ... continued below

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22 p.

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Last, Julie A.; Schroeder, Anne E.; Slade, Andrea Lynn; Sasaki, Darryl Yoshio; Yip, Christopher M. (University of Toronto, Toronto, Ontario, Canada) & Schoeniger, Joseph S. (Sandia National Laboratories, Livermore, CA) March 1, 2005.

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Description

Clostridial neurotoxins, such as botulinum and tetanus, are generally thought to invade neural cells through a process of high affinity binding mediated by gangliosides, internalization via endosome formation, and subsequent membrane penetration of the catalytic domain activated by a pH drop in the endosome. This surface recognition and internalization process is still not well understood with regard to what specific membrane features the toxins target, the intermolecular interactions between bound toxins, and the molecular conformational changes that occur as a result of pH lowering. In an effort to elucidate the mechanism of tetanus toxin binding and permeation through the membrane a simple yet representative model was developed that consisted of the ganglioside G{sub tlb} incorporated in a bilayer of cholesterol and DPPC (dipalmitoylphosphatidyl choline). The bilayers were stable over time yet sensitive towards the binding and activity of whole toxin. A liposome leakage study at constant pH as well as with a pH gradient, to mimic the processes of the endosome, was used to elucidate the effect of pH on the toxin's membrane binding and permeation capability. Topographic imaging of the membrane surface, via in situ tapping mode AFM, provided nanoscale characterization of the toxin's binding location and pore formation activity.

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22 p.

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  • Report No.: SAND2005-1700
  • Grant Number: AC04-94AL85000
  • DOI: 10.2172/922768 | External Link
  • Office of Scientific & Technical Information Report Number: 922768
  • Archival Resource Key: ark:/67531/metadc895119

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Office of Scientific & Technical Information Technical Reports

Reports, articles and other documents harvested from the Office of Scientific and Technical Information.

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  • March 1, 2005

Added to The UNT Digital Library

  • Sept. 27, 2016, 1:39 a.m.

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  • Dec. 2, 2016, 3:52 p.m.

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Last, Julie A.; Schroeder, Anne E.; Slade, Andrea Lynn; Sasaki, Darryl Yoshio; Yip, Christopher M. (University of Toronto, Toronto, Ontario, Canada) & Schoeniger, Joseph S. (Sandia National Laboratories, Livermore, CA). Toxin studies using an integrated biophysical and structural biology approach., report, March 1, 2005; United States. (digital.library.unt.edu/ark:/67531/metadc895119/: accessed September 23, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.