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A Bacterial Genotoxin

Many otherwise unrelated Gram-negative bacterial pathogens that cause a panoply of illnesses such as chancroid, endocarditis, diarrhea, periodontal disease, and chronic hepatitis, possess a related toxic activity on cultured cells. In epithelial cells, the activity typically manifests itself in an arrest at the G2 stage of the cell cycle, after which a gradual, progressive distention is observed that leads to the formation of giant cells which die after several days. This phenotype has given the name "cytolethal distending toxin" (CDT) to this activity. Intoxicated lymphocytes do not enlarge but instead die by apoptosis.

This toxic activity is associated with the products of an operon that encodes three proteins: CdtA, CdtB, and CdtC. These genes are found in a variety of pathogens, such as Escherichia coli, Shigella dysenteriae, Actinobacillus actinomycetemcomitans, Campylobacter spp. (C. jejuni and C. fetus), Helicobacter spp. (H. cinaedi, hepaticus, and pallorum), and Haemophilus ducreyi. The CdtB subunit, considered now to be the active component of the holotoxin within host cells, is also found in Salmonella typhi and paratyphi A.

The subunits CdtA and CdtC associate with the nuclease CdtB to form a holotoxin that translocates CdtB into the host cell, where it generates DNA lesions. The crystal structure of the holotoxin from Haemophilus ducreyi reveals that CDT consists of a modified deoxyribonuclease-I family enzyme bound to two ricin-like lectin domains. CdtA, CdtB, and CdtC form a ternary complex with three interdependent molecular interfaces characterized by globular as well as extensive non-globular, peptide interactions. The lectin subunits form a deeply grooved, highly aromatic surface that mutagenesis has shown to be critical for toxicity. The holotoxin possesses a steric block of the CdtB active site by a non-globular extension of the CdtC subunit, and the structure has identified a putative DNA binding pocket in CdtB that is essential for toxin activity.

 

D. Nesic, Y. Hsu, and C.E. Stebbins. (2004). "Assembly and function of a bacterial genotoxin." Nature, 429, 429-433.  [Abstract] [pdf] [pdb]
D. Nesic and C.E. Stebbins. (2005). "Mechanisms of Assembly and Cellular Interactions for the Bacterial Genotoxin CDT." PLoS Pathogens, Nov 18;1(3):e28.  [Abstract] [pdf]
X. Hu, D. Nesic, and C.E. Stebbins. (2006). "Comparative Structure-Function Analysis of Cytolethal Distending Toxins." PROTEINS, Feb 1;62(2):421-34.  [Abstract] [pdf]
X. Hu and C.E. Stebbins. (2006). "Dynamics and Assembly of the Cytolethal Distending Toxin." PROTEINS, Dec 1;65(4):843-55. PMID: 17034038  [Abstract] [pdf]

 

Dr. Dragana Nesic was the lead scientist on the CDT project.