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EcoSal Plus

Domain 8:

Pathogenesis

Heat-Labile Enterotoxins

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  • Authors: Michael G. Jobling1, and Randall K. Holmes2
  • Editor: Michael S. Donnenberg3
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Microbiology, University of Colorado Health Sciences Center, MS 8333, PO Box 6511, 12800 E. 19th Ave., Aurora, CO 80010; 2: Department of Microbiology, University of Colorado Health Sciences Center, MS 8333, PO Box 6511, 12800 E. 19th Ave., Aurora, CO 80010; 3: University of Maryland, School of Medicine, Baltimore, MD
  • Received 09 January 2006 Accepted 20 March 2006 Published 24 April 2006
  • Address correspondence to Randall K. Holmes Randall.Holmes@uchsc.edu.
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  • Abstract:

    Heat-labile enterotoxins (LTs) of are closely related to cholera toxin (CT), which was originally discovered in 1959 in culture filtrates of the gram-negative bacterium . Several other gram-negative bacteria also produce enterotoxins related to CT and LTs, and together these toxins form the - family of LTs. Strains of causing a cholera-like disease were designated enterotoxigenic (ETEC) strains. The majority of LTI genes () are located on large, self-transmissible or mobilizable plasmids, although there are instances of LTI genes being located on chromosomes or carried by a lysogenic phage. The stoichiometry of A and B subunits in holotoxin requires the production of five B monomers for every A subunit. One proposed mechanism is a more efficient ribosome binding site for the B gene than for the A gene, increasing the rate of initiation of translation of the B gene independently from A gene translation. The three-dimensional crystal structures of representative members of the LT family (CT, LTpI, and LTIIb) have all been determined by X-ray crystallography and found to be highly similar. Site-directed mutagenesis has identified many residues in the CT and LT A subunits, including His44, Val53, Ser63, Val97, Glu110, and Glu112, that are critical for the structures and enzymatic activities of these enterotoxins. For the enzymatically active A1 fragment to reach its substrate, receptor-bound holotoxin must gain access to the cytosol of target cells.

  • Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5

Key Concept Ranking

Type II Secretion System
0.42614478
Sodium Dodecyl Sulfate
0.33771175
Cyclic AMP
0.32061264
Amino Acids
0.31058604
Shiga Toxins
0.30565906
0.42614478

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/content/journal/ecosalplus/10.1128/ecosalplus.8.7.5
2006-04-24
2017-10-20

Abstract:

Heat-labile enterotoxins (LTs) of are closely related to cholera toxin (CT), which was originally discovered in 1959 in culture filtrates of the gram-negative bacterium . Several other gram-negative bacteria also produce enterotoxins related to CT and LTs, and together these toxins form the - family of LTs. Strains of causing a cholera-like disease were designated enterotoxigenic (ETEC) strains. The majority of LTI genes () are located on large, self-transmissible or mobilizable plasmids, although there are instances of LTI genes being located on chromosomes or carried by a lysogenic phage. The stoichiometry of A and B subunits in holotoxin requires the production of five B monomers for every A subunit. One proposed mechanism is a more efficient ribosome binding site for the B gene than for the A gene, increasing the rate of initiation of translation of the B gene independently from A gene translation. The three-dimensional crystal structures of representative members of the LT family (CT, LTpI, and LTIIb) have all been determined by X-ray crystallography and found to be highly similar. Site-directed mutagenesis has identified many residues in the CT and LT A subunits, including His44, Val53, Ser63, Val97, Glu110, and Glu112, that are critical for the structures and enzymatic activities of these enterotoxins. For the enzymatically active A1 fragment to reach its substrate, receptor-bound holotoxin must gain access to the cytosol of target cells.

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Figures

Image of Figure 1
Figure 1

Fifty bases of sequence (uppercase letters) is shown for the A2-B region of each enterotoxin gene. and , LTp-I; and , LTh-I; and , CT; IIa-A2 and IIa-B, LT-IIa; IIb-A2 and IIb-B, LT-IIb. Single-residue notations for amino acids are shown in lowercase letters below their respective codons. Overlaps between the DNA sequences of the A2 and B genes are shown in bold and include the ATG start codon of each B gene and the TGA or TAA stop codon of each A gene. Selected restriction sites are identified in italics. The overlap of these genes suggests translational coupling of the syntheses of the A and B polypeptides of these LTs.

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5
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Image of Figure 2
Figure 2

Sequences are labeled according to type followed by the strain designation. Residues distinguishing between type I variants are shown in red (porcinelike), green (humanlike), or magenta (CT specific). The consensus shows residues that are absolutely (*), strongly (:), or weakly (.) functionally conserved between all enterotoxins. The position of the disulfide bond between Cys187 and Cys199 (type I numbering) is also shown.

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5
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Image of Figure 3A
Figure 3A

Red or green residues are specific to porcine or human LT-I variants, respectively. Residues that differ between CT B polypeptides from Classical (569B) and El Tor (2125) biotypes of are colored magenta. The consensus shows residues that are absolutely (*), strongly (:), or weakly (.) functionally conserved between B subunits.

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5
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Image of Figure 3B
Figure 3B

Only residues completely conserved among all B subunits are colored magenta. The consensus shows residues that are absolutely (*), strongly (:), or weakly (.) functionally conserved among all enterotoxins.

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5
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Image of Figure 4
Figure 4

The A subunit sits on and penetrates a donut-shaped B pentamer responsible for binding to cell surface receptors. The single A subunit is divided into two polypeptides by proteolytic cleavage in the disulfide-bonded loop (S-S) between A1 and A2. The enzymatic A1 polypeptide is formed from an N-terminal globular enzymatic A1 subdomain (red) wrapped by an extended-chain A1subdomain (yellow) to a second hydrophobic globular C-terminal A1 subdomain (blue) that links to the A2 polypeptide (orange). The A1 polypeptide has extensive contacts with the N-terminal alpha-helical segment of the A2 polypeptide, and the C-terminal portion of the A2 polypeptide penetrates into the central pore of the B pentamer (shown as ribbons). A KDEL sequence (or a closely related sequence; in black) present at the C terminus of the A2 polypeptide functions as an ER retention sequence.

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5
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Image of Figure 5
Figure 5

Shown is a projection view of the pentamer viewed from below (with respect to the holotoxin) with beta-sheets drawn as large blue arrows and alpha-helices drawn as black barrels. The beta-sheets form a single 30-ladder circle, and the large alpha-helices line the central pore of the pentamer. Redrawn from reference 87 .

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5
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Image of Figure 6
Figure 6

Beta-sheets are colored to correspond to those in the OB fold ( 92 ). OS-GM1 is shown in stick format.

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5
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Image of Figure 7
Figure 7

(Top panel) A1 and A2 prior to activation, with covalent connections via their mutual peptide chain (black loop) and disulfide bond (orange line) intact. FY: Phe31,Tyr30. (Middle panel) Activation is initiated by cleavage of the peptide loop between A2 and A2 and reduction of the disulfide bond (i), which causes an indirect structural change in the environment of Tyr30 and Phe31 or in the hydrophobic patch (blue) contacted by these residues (ii). This change results in activation loop (red) disorder (iii), which in turn predisposes the active-site loop (green) toward disorder upon binding of NAD. (Bottom panel) In vivo, it is likely that A1 and A2 are physically separated shortly after reduction of the A1-A2 disulfide bond in the ER (iv), simplifying the concept of Tyr30/Phe31 pocket disruption. Reprinted from reference 86 with permission from the American Chemical Society.

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5
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Image of Figure 8
Figure 8

For a full description, see the text. An idealized enterotoxin is shown (B pentamer, dark blue; A2, dark green; A1, yellow). ?, unknown unfolding effector; magenta hexagons, ADP-ribosyl group; blue circle, Gsα; white ellipses, Gβ and Gγ; ADPrGsα, ADP-ribosylated Gsα; AdCy*, activated adenylate cyclase. Adapted and redrawn from reference 151 .

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5
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Image of Figure 9
Figure 9

(A) The CT subunit A1-ARF6-GTP heterodimer. Secondary structural elements of CT subunit A1 are labeled according to reference 87 . CT subunit A1 is gray, with important loop regions shown in gold (activation loop) and red (active-site loop). The mutated active-site residues, Asp110 and Asp112, are green sticks. ARF6 is yellow, with the bound GTP molecule as sticks. (B) CT subunit A1 in complex with CT subunit A2 (blue) from holo-CT. Conformational changes are limited to loop regions, colored as in panel A. Active-site loop residue Thr50 was disordered in the latent holo-CT structure ( 129 ); the analogous residue in other inactive holo-CT and LT structures displays increased levels of B factors relative to surrounding residues ( 86 , 87 ). (C) CT subunit A1 and ARF6-GTP interface residues in a ‘‘butterfly’’ representation. Most interactions of CT subunit A1 with ARF6-GTP occur within switch 1, interswitch, and switch 2 regions, but hydrogen bonds are also made to N-terminal residues Glu13 and Arg15 (gray). Each interacting residue is marked with a sphere at the Cα position, and CT subunit A1 residues are colored according to the ARF6-GTP region contacted. Reprinted from reference 196 with permission from the American Association for the Advancement of Science.

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5
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Image of Figure 10
Figure 10

Changes in loop regions of CT subunit A1 between holo-CT (left) and CT subunit A1-ARF6-GTP (right) lead to opening of the active site (green). Loops are colored as in Fig. 9 . Reprinted from reference 196 with permission from the American Association for the Advancement of Science.

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5
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Image of Figure 11
Figure 11

ARF6-GTP-bound CT subunit A1 in complex with its substrate, NAD. (A) A σA-weighted omit map contoured at 2.5 σ, showing density surrounding the NAD molecule in the CT subunit A1 active site. (B) Surface representation of the NAD-occupied CT subunit A1 active site (green), viewed from the top. The large active-site cleft is open to solvent from the top and from both ends. ARF6-GTP, in yellow, binds to CT subunit A1 (gray) far from the active site (green). The knob (red), formed by active-site loop residues 48 to 52 when CT subunit A1 is ARF bound, and the ARTT motif (brown) ( 201 ) form a surface for potential Gsα recruitment. (C) Stereoview of contacts between NAD and active-site residues (green sticks). Hydrogen bonds are indicated as black dashes. NAD makes extensive direct interactions with protein atoms but also recruits three water molecules and a glycerol molecule to mediate hydrogen bonds with the active site. Reprinted from reference 196 with permission from the American Association for the Advancement of Science.

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5
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Image of Figure 12
Figure 12

Bound NADconformations observed in ADPRTs. Views were created by superimposing structurally conserved active-site elements (rms deviations, 0.9 to 1.2 Å over ~20 Cα residues). Toxins are grouped according to quaternary-structure classification ( 202 ). The NMN moiety binds in a similarly compact fashion in all toxins, but the AMP moiety shows variation. Remarkably, in ADPRTs in the same structural family as CT, such as DT and exotoxin A, the adenine ribose is oriented differently, leading the adenine base to bind in a completely different manner from that in CT subunit A1. Reprinted from reference 196 with permission from the American Association for the Advancement of Science.

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5
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Tables

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Table 1

Amino acid heterogeneity among LT-I toxin A subunits

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5
Generic image for table
Table 2

Amino acid heterogeneity among LT-I toxin B subunits

Citation: Jobling M, Holmes R. 2006. Heat-Labile Enterotoxins, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.7.5

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