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Chapter 9 : Receptors for Bacterial Toxins

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Receptors for Bacterial Toxins, Page 1 of 2

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Abstract:

A review of Shiga toxin receptor, diphtheria toxin (DT) receptor, exotoxin A (PEA) receptors will illustrate the different ways these molecules are studied and that bacterial toxins have harnessed a variety of processes to enter target cells. Evidence presented by researchers that low-density lipoprotein receptor-related protein (LRP) serves as the receptor for PEA is several-fold. First, both the toxin-binding protein purified from LM cells or mouse liver and LRP have similar mobility on SDS-PAGE and are indistinguishable immunologically. Second, native PEA, but not a mutant toxin defective in its ability to bind to LM cells, binds to purified LRP that is immobilized on polystyrene or on nitrocellulose; the toxin interacts with the 515-kDa heavy chain of LRP on ligand blots, not with the 85-kDa light chain. Third, receptor-associated protein (RAP) both blocks binding of PEA to mouse LM cells and abolishes toxicity. Cells expressing receptors with different-length juxtamembrane domains bind DT normally; however, they exhibit reduced sensitivity to DT when compared to wild-type cells. The three receptors have functions essential to the normal physiologic properties of mammalian cells. Nevertheless, they represent molecules usurped by different bacterial toxins as the first step in the intoxication process. Cells lacking functional cell surface receptor are resistant to the toxin, expression of receptor correlates with the tissue specificity of toxin damage, and this in turn correlates with the disease symptoms seen in animal models and in patients.

Citation: Saelinger C. 2003. Receptors for Bacterial Toxins, p 131-148. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch9

Key Concept Ranking

Amino Acids
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Shiga Toxins
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Figures

Image of Figure 1
Figure 1

The figure depicts the binding and entry of BL22 into a leukemia cell expressing CD22. Once taken into an endosome, BL22 is processed by the cellular protease, furin. This is followed by the reduction of a key disulfide (Cys-265 to 287), the release of an enzymatically active C-terminal fragment, its translocation to the cytosol, and the cessation of protein synthesis. This causes death of the leukemia cell.

Citation: Saelinger C. 2003. Receptors for Bacterial Toxins, p 131-148. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch9
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Image of Figure 1
Figure 1

Structure of lowdensity LRP, the receptor for exotoxin A. LRP is a multifunctional scavenger receptor capable of binding a variety of ligands to different clusters of ligand-binding repeats. tPA, tissue plasminogen activator; LPL, lipoprotein lipase. From reference 2 with permission.

Citation: Saelinger C. 2003. Receptors for Bacterial Toxins, p 131-148. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch9
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Image of Figure 2
Figure 2

RAP blocks binding and toxicity of PEA for mouse LM fibroblasts. (A) Inhibition by RAP-GST of PEA binding to mouse LM cells. LM cell monolayers were incubated with medium containing RAP-GST (●) or GST (○) for 18 h at 4°C, followed by incubation with 2 g/ml of PEA for 5 h at 4°C. Cells were then washed, harvested, and homogenized, and the concentration of cellassociated toxin assayed by enzyme-linked immunosorbent assay. (B) RAP protects LM cells from PEA-induced toxicity. Various concentrations of RAP were preincubated with LM cells for 90 min at 37°C. Cells were cooled and 40 ng of PEA added. Protein synthesis was assessed by measuring incorporation of H-leucine into trichloroacetic acid-precipitable material. From reference 3 with permission.

Citation: Saelinger C. 2003. Receptors for Bacterial Toxins, p 131-148. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch9
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Image of Figure 3
Figure 3

Structure of the cell surfaceexpressed precursor form of the heparinbinding EGF-like growth factor, the DT receptor.

Citation: Saelinger C. 2003. Receptors for Bacterial Toxins, p 131-148. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch9
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Image of Figure 4
Figure 4

Proposed model for role of CD9 and heparin-like molecules in binding of DT to proHB-EGF. (a) ProHB-EGF alone in the plasma membrane cannot bind DT. (b) CD9 binds to and orients proHB-EGF so that it is accessible to DT. (c) Cell surface heparan-sulfate proteoglycans (HSPG) or free heparin binds to proHB-EGF at the heparin-binding domain and induces a conformational change; this change results in increased affinity of the receptor for DT. (d) The proHB-EGF/CD9-HSPG-DT complex is formed. From reference 8 with permission.

Citation: Saelinger C. 2003. Receptors for Bacterial Toxins, p 131-148. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch9
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Image of Figure 5
Figure 5

Structure of Gb3. Gb3 consists of a ceramide long-chain fatty acid that is embedded in the plasma membrane and a short extracellular trisaccharide chain ending in a digalactose residue. From reference 4 with permission.

Citation: Saelinger C. 2003. Receptors for Bacterial Toxins, p 131-148. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch9
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References

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1. Fuchs, G.,, M. Mobassaleh,, A. Donohue-Rolfe,, R. K. Montgomery,, R. J. Grand,, and G. T. Keusch. 1986. Pathogenesis of shigella diarrhea: rabbit intestinal cell microvillus membrane binding site for Shigella toxin. Infect. Immun. 53:372377.
2. Herz, J.,, and D. K. Strickland. 2001. LRP: a multifunctional scavenger and signaling receptor. J. Clin. Invest. 108:779784.
3. Kounnas, M. Z.,, R. E. Morris,, M. R. Thompson,, D. J. FitzGerald,, D. K. Strickland,, and C. B. Saelinger. 1992. The α2macroglobulin receptor/LDL receptor related protein binds and internalizes Pseudomonas exotoxin A. J. Biol. Chem. 267:1242012423.
4. Lingwood, C. A. 1996. Role of verotoxin receptors in pathogenesis. Trends Microbiol. 4:147152.
5. Middlebrook, J. L.,, R. B. Dorland,, and S. H. Leppla. 1978. Association of diphtheria toxin with Vero cells. J. Biol. Chem. 253:73257330.
6. Naglich, J. G.,, J. E. Metherall,, D. W. Russell,, and L. Eidels. 1992. Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell 69:10511061.
7. Obrig, T. G.,, P. J. Del Vecchio,, J. E. Brown,, T. P. Moran,, B. M. Rowland,, T. K. Judge,, and S. W. Rothman. 1988. Direct cytotoxic action of Shiga toxin on human vascular endothelial cells. Infect. Immun. 56:23722378.
8. Umata, T.,, K. D. Sharma,, and E. Mekada,. 1999. Diphtheria toxin and the diphtheria toxin receptor, p. 4566. In K. Aktories, and I. Just (ed.), Bacterial Protein Toxins. Springer-Verlag, Berlin, Germany.
1. O’Loughlin, E. V.,, and R. M. Robins-Browne. 2001. Effect of Shiga toxin and Shigalike toxins on eukaryotic cells. Microbes Infect. 3:493507.

Tables

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Table 1

Examples of ligands that bind the extracellular domain of LRP

Citation: Saelinger C. 2003. Receptors for Bacterial Toxins, p 131-148. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch9

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