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Cryo-electron Microscopy Identifies Lethal Anthrax Protein Complex

Health In Focus   - G J E 4
Highlights
  • Researchers identify key features in the anthrax protein complex that facilitate entry into host cell.
  • The toxin protein complex found to act as a 'conveyor belt' for bacterial entry.
  • The study provides insights into possible drug target.
Cryo-electron Microscopy Identifies Lethal Anthrax Protein Complex
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The three dimensional structure of the anthrax toxin that facilitates its entry into the cytoplasm of the cells have been published in a study in the the Journal of General Physiology detailing how the toxin behaves as a 'conveyor belt' for the entry of toxic enzymes into the cell.

‘Drug targets aimed at anthrax protein complex will control toxicity in anthrax.’
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Molecular Basis for Anthrax

Bacillus anthracis causes anthrax. This spore forming bacterium enters the animal or human and begins to rapidly attack the immune cells. The bacterium secretes three types of toxins that aid in overpowering the immune cells of the host;
  • Protective Antigen (PA)
  • Lethal Factor (LF)
  • Edema Factor (EF)
The main targets of these toxins are to attack the immune cells that ingest invading microorganisms like the macrophages and other defensive cells.

Mode of Action

The three toxins are potent when they act together, but are not toxic when they are present separately.

Function of
  • PA: The LF and EF have to combine with PA to be lethal. It facilitates the entry of the other toxins into the cell.
  • LF: Responsible for converting adenosine triphosphate (ATP) in the cell into cyclic adenosine monophosphate (AMP).
  • EF: This toxin disables a family of signaling proteins, MAPKKs
The three toxins combine to form a lethal complex that results in the destruction of the host cells due to disruption in many signaling pathways.

Mechanism of Entry into the Host Cell

The three toxins combine to form a prepore complex that facilitates the entry of the toxin into the cell. This structure was studied by McGill University's Dr. Isabelle Rouiller and Sanford Burnham Prebys Medical Discovery Institute, Dr. Robert Liddington and colleagues using a cryo-electron microscopy.

The Mechanism of Entry Known so Far

The PA, LF, EF complex bind to a receptor on the surface of the host cell, while an enzyme secreted by the host cell cleaves a portion of PA. The toxic complex then attach to six other PA molecules to form a ring like structure. The host then engulfs this complex and takes the toxin into the cell using endocytosis.

A bubble like structure takes the toxin into the cell, where the toxin changes shape and then begins to attack the cell when the endosome diffuses

Current Understanding of Toxin Entry Using Cryo-electron Microscopy

The map provided by cryo-electron microscopy found
  • 7 PA were found around a narrow pore.
  • 3 LF proteins were found at the rim of the pore.
  • Each LF molecule was bound to the PA subunit and to its clockwise neighbour.
Functions of these Inter LF Interactions
  • Prevents the toxic enzymes from unfolding prematurely.
  • Holds the toxic enzymes in place.
Mechanism of Entry Identified by Cryo-electron Microscopy
  • When the first LF molecule begins to enters the cell, the next LF molecule is destabilized to facilitate its entry into the cell.
  • LF molecules that are present in addition could then bind to the spots that were vacated on the pore's rim. This will lead to a continuous entry of LF molecules, as envision by electrophysiological studies.
Dr. Rouiller added "We have demonstrated that the anthrax pore can translocate full-length LF in a highly efficient, fast, and robust fashion. The pore can effectively remain fully loaded for extended periods, acting as a conveyer belt while translocating a continuous 'daisy chain' of deadly LF molecules."

Bacillus anthracis is a rod shaped bacterium that exists as spores when the conditions are not viable for its survival as a normal cell. An individual is infected with anthrax when the spore is inhaled into the body. The bacterium then rapidly divides from the spore with multiple bacteria entering the blood stream.

The most important aspect of a bacterial invasion by Bacillus anthracis is the secretion of the toxins, since antibiotic therapy will clear the bacteria from the blood stream but not the toxins, alternate drug targets that are aimed at the toxin is essential for control of the disease and the symptoms produced. The mechanism of entry of the toxins discovered through cryo-electron microscopy provides greater insight into possible drug targets.

References:
  1. Anthrax - Basics - (https:www.cdc.gov/anthrax/basics/)
  2. Anthrax Lethal Factor - (https:www-ssrl.slac.stanford.edu/research/highlights_archive/anthrax.html)
  3. Molecular Basis for Anthrax Intoxication - (http://www.ks.uiuc.edu/Research/anthrax/)
Source: Medindia
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