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Identification of the Regions of Cytotoxic Necrotizing Factor Type 1 Responsible for Receptor Binding and Enzymatic Activity

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Technical Report

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Uniformed Services University Of The Health Sciences Bethesda United States

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Uropathogenic Escherichia coli UPEC cause the majority of uncomplicated urinary tract infections UTIs in the United States. UPEC express a number of virulence factors, including type 1 and P fimbriae, hemolysin, and Cytotoxic Necrotizing Factor type 1 CNF1 that are associated with the capacity of the organism to colonize the human urinary tract and cause cystitis andor pyelonephritis. CNF1 is a cytoplasmic polypeptide toxin that is composed of a reputed N-terminal binding domain and a C-terminal enzymatic domain. A putative transmembrane domain, considered to be responsible for translocation of the toxin into eukaryotic cells, is contained within the N-terminal half of the molecule. CNF1 belongs to the family of Rho-activating toxins and deamidates glutamine-63 Gln63 of RhoA and Gln61 of Rac1 and Cdc42. These deamidation reactions lead to the constitutive activation of the Rho GTPases and the subsequent upregulation of downstream cellular effectors of those molecules. The CNF1-mediated effects on eukaryotic cells result from specific binding to the target cell, translocation across the host membrane, trafficking within the cytoplasm, and enzymatic modification of the GTPase substrates. The regions within the toxin responsible for each step in intoxication of the host cell are only roughly delineated in fact, only the C-terminus of CNF1 has been crystallized. In this study, I sought to more precisely define the area of CNF1 that is responsible for its enzymatic activities as well as the region ofthe toxin that binds to its receptor, laminin receptor precursor protein LRP.

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