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Introduction

Cholix toxin (CT) are a class of protein toxin originating from the bacteria Vibrio Cholerae. The toxin uses ADP-riboyltransferase to inactivate eukaryotic elongation factor 2 by transferring ADP-ribose from NAD+ which inhibits protein synthesis and causes cell death. This protein toxin has been known to cause disease in both plants and animals. Specifically, the toxin can cause the disease Cholera. It enters eukaryotic cells through endocytosis. Once inside, the toxin transfers an ADP-ribose group to an Arg residue of the GTP binding protein G. This then activates adenylate cyclase which leads to an increase amount of cAMP, causing a secretion of Cl-,HCO3-, and water from epithelial cells from the site of colonization. The result is dehydration and loss of electrolytes in mammals. Cholix toxins are composed of a receptor binding, translocation, and catalytic domain.

Structure

To observe the structure, the Cholix Toxin was crystallized by vapor diffusion against reservoirs containing 23% polyethlene gylcol-10,000, 7.5% ethylene glycol, and 0.1 m HERPES. In addition, the reservoirs were kept at a of pH 7.5 and at a temperature of 19°C. About 40 µL of reservior solution containg 1.25 mM NAD+ solution was added to a 2 µL crystal containg droup. The NAD+ was allowed to soak into the crystals for approximately 2-3 minutes. The crystals were then transffered to paratone-N for visualization.

Cholix Toxin contains three different domains. Domain I is the receptor binding domain containing two beta sheets. Domain II is the translocation domain containing a bundle of six . Domain III is considered the catalytic domain and consists of antiparallel .

Mechanism of Action

The mechanism for the cholix toxin occurs as follows:

1. The Cholix Toxin binds to the GM1 of host cell membrane.
2. Toxin gains access inside the cell through cell mediated endocytosis.
3. CT-GM1 complex forms
4. CT-GM1 complex travels through the Golgi body and to the Endoplasmic Reticulum (ER)
5. The Alpha-1 subunit of the toxin will unfold and dissociated from B pentamer
6. The unfolded A1 is translocated to the cystol

Image:Cholix Toxin.jpg

Medical Implications or Possible Applications

References

1. The 1.8A Cholix Toxin Crystal Structure in Complex with NAD+ and Evidence for a New Kinetic Model