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Chapter 20 : Bacterial Toxins that Modulate Rho GTPase Activity

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Bacterial Toxins that Modulate Rho GTPase Activity, Page 1 of 2

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Abstract:

This chapter describes a distinct class of toxins that mimic endogenous regulatory factors of Rho GTPases. The actions of bacterial toxins are noncovalent and are therefore reversible. These ‘‘modulating toxins’’ encode domains that function as guanine nucleotide exchange factors (GEFs) or as GTPase-activating proteins (GAPs). The study of bacterial GEFs and GAPs is shedding new light on mechanisms of bacterial pathogenesis. Binding of GTP to the nucleotide-free form of the GTPase is favored by a high cytoplasmic concentration of GTP relative to GDP. Three types of endogenous eukaryotic proteins regulate GTPase cycling between GTP-bound and GDPbound forms. The rate of GTP hydrolysis is accelerated by interaction with GAPs. GAPs act in two ways to increase GTPase activity. The first involves the positioning of a nucleophilic water molecule that attacks theγ-phosphate of GTP. Second, GAPs donate a catalytic arginine residue that is needed to complete the active site of the GTPase. Several toxins secreted by type III systems have GAP activity for Rho GTPases. These are SptP from , ExoS and ExoT from , and YopE from , , and . A major difference between them is that ExoT possesses only about 0.2% of the catalytic ADP-ribosyltransferase activity of ExoS. The three-dimensional structures of ExoS bound to Rac1 and SptP bound to Rac1 in the presence of GDP have been determined.

Citation: Bliska J, Viboud G. 2003. Bacterial Toxins that Modulate Rho GTPase Activity, p 283-291. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch20.

Key Concept Ranking

Mitogen-Activated Protein Kinase Pathway
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Type III Secretion System
0.48827782
Bacterial Pathogenesis
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Salmonella enterica
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Figures

Image of Figure 1
Figure 1

Factors that modulate Rho GTPase activity. As shown for Rac1, Rho GTPases cycle between an active GTP-bound form (diamond) and an inactive GDP-bound form (oval). GEFs facilitate the release of GDP and the binding of GTP by Rac1. The active form of Rac1 interacts with effector proteins to stimulate cellular responses. GAPs accelerate hydrolysis of GTP. Rac1 is maintained in the inactive form by interaction with GDIs. The sp. proteins SopE and SopE2 function as GEFs for Rac1 and Cdc42. sp. SptP functions as a GAP for Rac1 and Cdc42. sp. ExoS and ExoT and sp. YopE function as GAPs for Rac1, Cdc42, and RhoA.

Citation: Bliska J, Viboud G. 2003. Bacterial Toxins that Modulate Rho GTPase Activity, p 283-291. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch20.
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Image of Figure 2
Figure 2

Physical organization of toxins with GEF or GAP domains. The sp. SopE and SopE2 proteins contain a single GEF domain. sp. SptP is a bifunctional toxin with an amino-terminal GAP domain and a carboxy-terminal PTP domain. sp. YopE contains a single GAP domain. ExoS and ExoT of sp. are bifunctional, with amino-terminal GAP and carboxy-terminal ADP-ribosyltransferease (ART) domains. The aminoterminal sequences of these bacterial toxins (thin black lines) contain signals for recognition and transport by type III secretion systems.

Citation: Bliska J, Viboud G. 2003. Bacterial Toxins that Modulate Rho GTPase Activity, p 283-291. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch20.
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Image of Figure 3
Figure 3

Alignment of the arginine finger motif of Rho GAPs with sequences of ExoS, SptP, and YopE. The bottom line shows a consensus sequence obtained by alignment of 15 Rho GAPs of eukaryotic origin ( ). Sequences from SptP, ExoS, and YopE are shown aligned with this consensus sequence. Invariant residues are shown in bold; a, aromatic; h, hydrophobic.

Citation: Bliska J, Viboud G. 2003. Bacterial Toxins that Modulate Rho GTPase Activity, p 283-291. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch20.
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Image of Figure 4
Figure 4

Secondary and tertiary structure of the GAP domain of ExoS. (a) Ribbon diagram of the GAP domain of ExoS in a complex with Rac1, GDP, and aluminum fluoride (AlF3). AlF3 is required to trap the ExoS-Rac1 complex in a transition state. Rac1 is colored blue. Bulge I is colored red, and bulge II is colored green in ExoS. The catalytic arginine in ExoS (Arg-146), the GDP, and the AlF3 are shown as ball-andstick models. (b) Secondary structure assignments for ExoS GAP domain and sequence alignments of ExoS, ExoT, YopE, and SptP. Invariant residues are shown as white on green or red (catalytic Arg). Asterisks and plus signs indicate residues involved in hydrophilic or hydrophobic interactions, respectively. G indicates residues that contact GDP. Reprinted from reference with permission. (See Color Plates following p. 256.)

Citation: Bliska J, Viboud G. 2003. Bacterial Toxins that Modulate Rho GTPase Activity, p 283-291. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch20.
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References

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1. Barbieri, J. T. 2000. Pseudomonas aeruginosa exoenzyme S, a bifunctional type-III secreted cytotoxin. Int. J. Med. Microbiol. 290:381387.
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13. Wallis, T. S.,, and E. E. Galyov. 2000. Molecular basis of Salmonella-induced enteritis. Mol. Microbiol. 36:9971005.
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Tables

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Table 1

Functional comparison of Rho GAP domains in bacterial toxins

Citation: Bliska J, Viboud G. 2003. Bacterial Toxins that Modulate Rho GTPase Activity, p 283-291. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch20.

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