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Chapter 14 : Membrane-Damaging Toxins:Family of RTX Toxins

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Membrane-Damaging Toxins:Family of RTX Toxins, Page 1 of 2

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Abstract:

The major cellular effect of RTX toxins has been ascribed to their pore-forming capacity, resulting in plasma membrane lesions and osmotic lysis. One group of RTX toxins consists of hemolysins, such as α-hemolysin (HlyA) and (ApxIA), that are toxic for a wide range of cell types from various species including humans and ruminants. The other category embraces leukotoxins produced by (LtxA) and (LktA), which display a more restricted target cell cytolytic activity. Both the number and the length of the fatty acyl groups differ among the RTX toxins. The characteristic feature of RTX toxins is a Ca-binding repeat domain (GGXGXDXUX, where U represents a large hydrophobic residue and X represents any amino acid) located in the C-terminal part of the protein. More recently, data have been presented that suggest that RTX toxins also affect intracellular signaling pathways without causing lysis of the cells. High doses of RTX toxins result in oligomerization and formation of large transmembrane pores that could be responsible for an extremely rapid destruction of the target cell membrane, providing no time for the host cell to defend itself by induction of the inflammatory response or apoptosis. The role of two RTX toxins in the urinary and respiratory tract, respectively, is finally reviewed in the chapter.

Citation: Oxhamre C, Richter-Dahlfors A. 2003. Membrane-Damaging Toxins:Family of RTX Toxins, p 203-214. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch14

Key Concept Ranking

Adenylate Cyclase Toxin
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Bacterial Virulence Factors
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Figures

Image of Figure 1
Figure 1

The Hly operon. The operon responsible for secretion of active HlyA from consists of four linked genes, . The gene (1,321 to 4,395 amino acids [aa]) is the structural gene encoding the immature and nonactive proHlyA. This immature form of the toxin undergoes posttranslational maturation by the action of (796 to 1,308 aa). Two genes, (4,468 to 6,591 aa) and (6,610 to 8,046 aa), encode membrane proteins that are involved in extracellular translocation of the hemolytic active HlyA toxin. Located approximately 1.5 kbp upstream of is , which acts as an enhancing sequence.

Citation: Oxhamre C, Richter-Dahlfors A. 2003. Membrane-Damaging Toxins:Family of RTX Toxins, p 203-214. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch14
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Image of Figure 2
Figure 2

Linear model of HlyA. RTX toxins contain three functional domains. The hydrophobic region of HlyA is subdivided into three domains, DI to DIII (amino acids 238 to 410), which are involved in the formation of transient pores in target cell membranes. Inactive proHlyA is posttranslationally modified by covalent attachment of two fatty acyl chains to Lys-564 and Lys-690. The fatty acyl groups are required to achieve hemolytic activity. The Ca-binding repeat domain is common in all RTX toxins. Upon binding of Cathe repeat domain mediates conformational changes of the tertiary structure of the toxin and enables it to interact with the target cell membrane. The transport signal sequence, together with HlyB, HlyD, and the outer membrane protein TolC, is required for secretion of HlyA.

Citation: Oxhamre C, Richter-Dahlfors A. 2003. Membrane-Damaging Toxins:Family of RTX Toxins, p 203-214. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch14
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Image of Figure 3
Figure 3

Linear model of AC toxin. Organization of the functional domains in CyaA resembles that of HlyA, e.g., a hydrophobic domain, a covalently attached fatty acyl chain, a Ca-binding repeat domain, and an export signal sequence. In addition, CyaA contains an adenylate cyclase (AC) enzymatic domain located in the very N-terminal part of the protein. The hydrophobic domains of CyaA are involved in the hemolytic activity of the toxin and are required for the delivery of the AC enzymatic domain into the cytosol of the target cell.

Citation: Oxhamre C, Richter-Dahlfors A. 2003. Membrane-Damaging Toxins:Family of RTX Toxins, p 203-214. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch14
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Download as Powerpoint

References

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1. Andersen, C.,, C. Hughes,, and V. Koronakis. 2000. Chunnel vision. Export and efflux through bacterial channel-tunnels. EMBO Rep. 1(4):313318.
2. Ladant, D.,, and A. Ullmann. 1999. Bordetella pertussis adenylate cyclase: a toxin with multiple talents. Trends Microbiol. 7(4):172176.
3. Ludwig, A.,, A. Schmid,, R. Benz,, and W. Goebel. 1991. Mutations affecting pore formation by haemolysin from Escherichia coli. Mol. Gen. Genet. 226:198208.
4. Schindler, S.,, A. Zitzer,, B. Schulte,, A. Gerhards,, P. Stanley,, C. Hughes,, V. Koronakis,, S. Bhakdi,, and M. Palmer. 2001. Interaction of Escherichia coli hemolysin with biological membranes. A study using cysteine scanning mutagenesis. Eur. J. Biochem. 268: 800808.
5. Stanley, P.,, V. Koronakis,, and C. Hughes. 1998. Acylation of Escherichia coli hemolysin: aunique protein lipidation mechanism underlying toxin function. Microbiol. Mol. Biol. Rev. 62(2):309333.
6. Uhlén, P.,, Å. Laestadius,, T. Jahnukainen,, T. Söderblom,, F. Bäckhed,, G. Celsi,, H. Brismar,, S. Normark,, A. Aperia,, and A. Richter-Dahlfors. 2000. Alpha-haemolysin of uropathogenic E. coli induces Ca²+ oscillations in renal epithelial cells. Nature 405: 694697.
7. Welch, R. A. 2001. RTX toxin structure and function: a story of numerous anomalies and few analogies in toxin biology. Curr. Top. Microbiol. Immunol. 257:85111.

Tables

Generic image for table
Table 1

Members of the RTX family

Citation: Oxhamre C, Richter-Dahlfors A. 2003. Membrane-Damaging Toxins:Family of RTX Toxins, p 203-214. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch14

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