VRC01 gp120 complex

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The crystal structure of ToxT is resolved in monomeric form, after isolation from Vibrio cholerae strain O395.[1]

Contents

Introduction

ToxT is a molecule at the end of a transcriptional cascade that autoregulates the transcription of the primary virulence factors of Vibrio cholerae[1] and itself. ToxT is a cytoplasmic protein that is activated in turn by ToxR, which is itself activated by ToxS in response to environmental stimuli.[2] These two factors, cholera toxin (CT)[2] and the toxin co-regulated pilus (TCP), are instrumental in causing the disease cholera[3]. This is an intestinal infection resulting in massive water loss in the affected individual, causing extreme dehydration.[4] Rehydration is sufficient as treatment.

ToxT complex with palmitoleic acid, 1.9 Angstrom resolution crystal structure, 3gbg

Drag the structure with the mouse to rotate


Further Study

Conclusive results about what activates ToxT itself has not yet been found. The varying activity of ToxT dependent on the presence of cis-palmitoleate or other unsaturated fatty acids represents a detailed method of effective pathogenicity in humans, but may not be a reasonable target for drug treatment. By restricting transcription (and thus translation and protein production) of virulence genes until the bacterium is determined to be in a favorable location for infection, Vibrio cholerae avoids wasting energy producing virulence factors that will just be cleared by the intestine. This is a specific mechanism to ensure that the bacterium also injects CT and TCP where they will do the most damage, perpetuating the infection. [6] Despite the lack of information about what activates ToxT itself, it is understood that the transcription of ctxA and tcpA by vibrio cholerae is sharply reduced in the presence of oleic, linoleic acid, and arachidonic acid, all of which are components of bile. Therefore, one may hypothesize that it may be possible to use the structure of a UFA or SFA to design a small molecule inhibitor of ToxT which may be used to treat or prevent cholera.


Evolution

Vibrio cholerae is a highly diverse species in which some strains are completely harmless, whereas other strains have the capacity to cause global cholera pandemics. It has been discovered that in each epidemic and pandemic strain, there is a chromosomal pathogenicity island (PAI) that is not present in the nonpathogenic strains. The region containing two ToxR-regulated genes (aldA and tagA) is composed of 13kb of previously unidentified DNA. [7]This region is part of a PAI that contains ToxT and a gene cluster a critical colonization factor and TCP. The PAI is 39.5 kb long, contains putative integrase and transposase genes, and inserts near a 10Sa RNA gene. One may infer that the PAI could have originated from a bacteriophage. This PAI was also found in two non-O1/non-O139 (which are both pandemic) sero type strains. Therefore, one may hypothesize that the PAI could be transferred within other strains of Vibrio cholerae.

Centroid RNA 1xtc
Centroid RNA 1xtc

RNA Structure

Here we have the centroid structure of the mRNA of ToxT. This mRNA is shown in its most stable conformation, with the less stable, higher energy regions in red. The lighter colored regions are more stable and lower in energy.

References

Proteopedia Page Contributors and Editors (what is this?)

Amanda Valdiosera, Michal Harel, Chris Casey, Alexander Berchansky

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