ToxT

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A nine-stranded beta sheet sandwich<!--insert scene here!--> contains a binding pocket that contains a ligand: cis-palmitoleate,<!--insert scene here!--> <ref name="structure">PMID: 20133655</ref> which appears to have a negative effect on virulence when present in vitro. This unsaturated fatty acid, like other UFAs,[http://http://en.wikipedia.org/wiki/Fatty_acid#Unsaturated_fatty_acids] tend to inhibit genes under the control of ToxT.
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A nine-stranded beta sheet sandwich<!--insert scene here!--> contains a binding pocket that contains a ligand: <i>cis</i>-palmitoleate,<!--insert scene here!--> <ref name="structure">PMID: 20133655</ref> which appears to have a negative effect on virulence when present in vitro. This unsaturated fatty acid, like other UFAs,[http://http://en.wikipedia.org/wiki/Fatty_acid#Unsaturated_fatty_acids] tend to inhibit genes under the control of ToxT.
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Specifically, the cis-palmitoleate appears to bind directly to ToxT, change its conformation, and thus lower the ability to bind DNA and form dimers.<ref name="structure">PMID: 20133655</ref>
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Specifically, the <i>cis</i>-palmitoleate appears to bind directly to ToxT, change its conformation, and thus lower the ability to bind DNA and form dimers.<ref name="structure">PMID: 20133655</ref>
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Revision as of 00:12, 27 November 2011

ToxT, 1.9 Angstrom resolution crystal structure

Drag the structure with the mouse to rotate

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. 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]

Structural Features

ToxT belongs to a family of transcriptional regulators known as AraC.[1] The AraC family is defined by a 100 amino acid region of sequence similarity that forms a DNA-binding domain with two helix-turn-helix motifs. [2] The two HTH regions are linked by another alpha helix, which is very polar.

A nine-stranded beta sheet sandwich contains a binding pocket that contains a ligand: cis-palmitoleate, [1] which appears to have a negative effect on virulence when present in vitro. This unsaturated fatty acid, like other UFAs,[5] tend to inhibit genes under the control of ToxT. Specifically, the cis-palmitoleate appears to bind directly to ToxT, change its conformation, and thus lower the ability to bind DNA and form dimers.[1]

Though the structure shown is a monomer with two overall domains (N-terminal and C-terminal), ToxT tends to form a dimer. The preferred state of ToxT varies between promoters, but binding to the ctx promoter to generate cholera toxin appears to be possible only in the dimer form. [3]

References

  1. ↑ 1.0 1.1 1.2 Lowden MJ, Skorupski K, Pellegrini M, Chiorazzo MG, Taylor RK, Kull FJ. Structure of Vibrio cholerae ToxT reveals a mechanism for fatty acid regulation of virulence genes. Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):2860-5. Epub 2010 Feb 1. PMID:20133655
  2. ↑ Martin RG, Rosner JL. The AraC transcriptional activators. Curr Opin Microbiol. 2001 Apr;4(2):132-7. PMID:11282467
  3. ↑ Shakhnovich EA, Hung DT, Pierson E, Lee K, Mekalanos JJ. Virstatin inhibits dimerization of the transcriptional activator ToxT. Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2372-7. Epub 2007 Feb 5. PMID:17283330 doi:10.1073/pnas.0611643104
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