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Chapter 15 : Bacterial Toxins that Covalently Modify Eukaryotic Proteins by ADP-Ribosylation

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Abstract:

The study of ADP-ribosylating toxins has advanced our understanding of bacterial pathogenesis and provided insight into the molecular basis of eukaryotic physiology, especially G-protein-coupled signal transduction. The pathology associated with an ADP-ribosylating toxin is due to alterations in the activity of specific eukaryotic proteins. To date, essentially all of the eukaryotic proteins that are ADP-ribosylated by bacterial toxins are nucleotide-binding proteins, most often GTP-binding proteins. Two types of activation have been observed, covalent modification and association with eukaryotic proteins or cofactors. The study of bacterial toxins involves a sequential evolution of knowledge and strategies. First, the toxin is isolated and its catalytic and intoxication mechanisms determined; next, strategies are developed to determine whether the toxin is a useful vaccine candidate by empirically attempting to chemically or genetically inactivate the toxin while retaining its immunogenicity. The final stage in toxin research is to determine whether it can be used as a pharmacological reagent. Continued studies on the eukaryotic mono-ADP ribosylating enzymes should provide new insight into how the posttranslational modification regulates cell physiology, as studies on bacterial ADP-ribosylating toxins have contributed to our understanding of bacterial pathogenesis. Polyacrylamide gel electrophoresis techniques have been used for the measurement of the kinetics of in vivo ADP-ribosylation of eukaryotic proteins by other bacterial toxins. Although ADP-ribosylation of eukaryotic proteins represents the first covalent modification attributed to a bacterial toxin, subsequent studies have identified additional covalent and noncovalent modifications catalyzed by bacterial toxins.

Citation: Barbieri J, Burns D. 2003. Bacterial Toxins that Covalently Modify Eukaryotic Proteins by ADP-Ribosylation, p 215-228. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch15

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Figures

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Figure 1

The three-dimensional structure of bacterial toxins provides insight into the organization and function of the AB domains. (Top) Diphtheria toxin. Although biochemical studies predicted that bacterial toxins had a discrete functional organization, solving the threedimensional structure of several bacterial toxins verified that these domains were distinct but at the same time interactive. Examination of each toxin's crystal structure provided the framework to predict how the domains interacted and how each domain performed its biological function. Assessment of the crystal structure of diphtheria toxin provided insight into the organization and function of the translocation domain and how this domain interacted with the membranes of the endosome to transport the A domain into the cell cytosol. Adapted from reference 3. (Bottom) Heat-labile enterotoxin of . Although it was apparent that the A domains of cholera toxin and the heat-labile enterotoxin of were cleaved by proteases into A and A peptides, the physical relationships between A and A and the B domain were not resolved solely by biochemical characterization. The three-dimensional structure of the heat-labile enterotoxin showed that the A peptide interacted with the A peptide and the B domain and that the C-terminal residues of the A peptide entered the central hole of the B domain. This structure provided a framework to predict how the AB toxins bind and enter the eukaryotic cell. Structures were obtained from the Protein Data Bank: 1SGK (from reference ) and 1LTS (from reference ), and edited with RasTool.

Citation: Barbieri J, Burns D. 2003. Bacterial Toxins that Covalently Modify Eukaryotic Proteins by ADP-Ribosylation, p 215-228. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch15
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Image of Figure 2
Figure 2

Photochemical cross-linking of the nicotinamide ring of NAD to a decarboxylated γ-carbonyl of the active-site glutamic acid of an ADPribosylating toxin. Adapted with permission from reference .

Citation: Barbieri J, Burns D. 2003. Bacterial Toxins that Covalently Modify Eukaryotic Proteins by ADP-Ribosylation, p 215-228. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch15
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Image of Figure 3
Figure 3

The primary amino acid sequences of the A domains of bacterial toxins include sequential regions of limited homology (regions 1, 2, and 3). Active site of diphtheria toxin cocrystalized with an NAD analog (shaded). Bacterial ADP-ribosylating toxins contain (in black): region 1 (a basic amino acid, either histidine or arginine at the N terminus), region 2 (a structural motif that is organized in -strand–-helical structure located within the central portion of the A domain), and region 3 (a catalytic glutamic acid, or diglutamic acid, located in the C terminus of the A domain). Structure (1DTP) obtained from the Protein Data Bank was deposited by M. S. Weiss and D. Eisenberg, and edited with RasTool.

Citation: Barbieri J, Burns D. 2003. Bacterial Toxins that Covalently Modify Eukaryotic Proteins by ADP-Ribosylation, p 215-228. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch15
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References

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1. Bell, C. E.,, and D. Eisenberg. 1997. Crystal structure of nucleotide-free diphteria toxin. Biochemistry 36:481488.
2. Carroll, S. F.,, J. A. McCloskey,, P. F. Crain,, N. J. Oppenheimer,, T. M. Marschner,, and R. J. Collier. 1985. Photoaffinity labeling of diphtheria toxin fragment A with NAD: structure of the photoproduct at position 148. Proc. Natl. Acad. Sci. USA 82:72377241.
3. Choe, S.,, M. J. Bennett,, G. Fujii,, P. M. Curmi,, K. A. Kantardjieff,, R. J. Collier,, and D. Eisenberg. 1992. The crystal structure of diphtheria toxin. Nature 357:216222.
4. Domenighini, M.,, and R. Rappuoli. 1996. Three conserved consensus sequences identify the NAD-binding site of ADP-ribosylating enzymes, expressed by eukaryotes, bacteria and T-even bacteriophages. Mol. Microbiol. 21:667674.
5. Sixma, T. K.,, K. H. Kalk,, B. A. van Zanten,, Z. Dauter,, J. Kingma,, B. Witholt,, and W. G. Hol. 1993. Refined structure of Escherichia coli heat-labile enterotoxin, a close relative of cholera toxin. J. Mol. Biol. 230:890918.
6. Sixma, T. K.,, S. E. Pronk,, K. H. Kalk,, E. S. Wartna,, B. A. van Zanten,, B. Witholt,, and W. G. Hol. 1991. Crystal structure of a cholera toxin-related heat-labile enterotoxin from E. coli. Nature 351:371377.
1. Collier, R. J. 1975. Diphtheria toxin: mode of action and structure. Bacteriol. Rev. 39: 5485.
2. Kahn, R. A.,, and A. G. Gilman. 1986. The protein cofactor necessary for ADPribosylation of Gs by cholera toxin is itself a GTP binding protein. J. Biol. Chem. 261: 79067911.
3. Tamura, M.,, K. Nogimori,, S. Murai,, M. Yajima,, K. Ito,, T. Katada,, M. Ui,, and S. Ishii. 1982. Subunit structure of islet-activating protein, pertussis toxin, in conformity with the A-B model. Biochemistry 21:55165522.

Tables

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Table 1

Members of the family of bacterial ADP-ribosylating toxins

Citation: Barbieri J, Burns D. 2003. Bacterial Toxins that Covalently Modify Eukaryotic Proteins by ADP-Ribosylation, p 215-228. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch15

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