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Chapter 20 : Bacterial Toxins that Modulate Rho GTPase Activity
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 Salmonella enterica, ExoS and ExoT from Pseudomonas aeruginosa, and YopE from Yersinia pestis, Y. pseudotuberculosis, and Y. enterocolitica. 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.