Actin‐ADP‐Ribosylating Toxins: Cytotoxic Mechanisms of<i>Clostridium botulinum</i>C2 Toxin and<i>Clostridium perfringens</i>lota Toxin

Aktories, Klaus; Sehr, Peter; Just, Ingo

doi:10.1002/9783527614615.ch8

Cited by 4 publications

(3 citation statements)

References 38 publications

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“…Some human pathogens have capitalized on this Achilles' heel and modulate the structure and function of eukaryotic actin either by direct ADP ribosylation of specific arginine residues on actin itself or by ADP ribosylation of arginine residues on proteins, such as rho, that control actin polymerization. The net result is massive depolymerization of this vital structural and signaling protein (reviewed in [43]). …”

Section: Discussionmentioning

confidence: 99%

“…Actin participates in numerous vital cellular functions, such as migration, phagocytosis, signaling, secretion, and intracellular transport (reviewed in [43]). Some human pathogens have capitalized on this Achilles' heel and modulate the structure and function of eukaryotic actin either by direct ADP ribosylation of specific arginine residues on actin itself or by ADP ribosylation of arginine residues on proteins, such as rho, that control actin polymerization.…”

Section: Discussionmentioning

confidence: 99%

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Molecular Epidemiology ofngaand NAD Glycohydrolase/ADP‐Ribosyltransferase Activity amongStreptococcus pyogenesCausing Streptococcal Toxic Shock Syndrome

Stevens

Salmi²,

McIndoo³

et al. 2000

J INFECT DIS

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Severe invasive group A streptococcal (GAS) infections emerged in the late 1980s, yet no single virulence factor has been common to all isolates from infected patients. A strong association was recently found between isolates of such cases (regardless of M type) and the production of NAD glycohydrolase (NADase). Of interest, all M-1 strains isolated after 1988 were positive for NADase, whereas virtually all M-1 GAS were previously negative for NADase. Genetic analysis demonstrated that GAS isolates were >96% identical in nga and >99% identical in their upstream regulatory sequences. Furthermore, because NADase-negative strains did not produce immunoreactive NADase, we concluded that additional regulatory element(s) control NADase production. NADase purified from GAS altered neutrophil-directed migration and chemiluminescence responses and had potent ADP-ribosyltransferase activity. In summary, the temporal relationship of NADase expression, alone or with other streptococcal virulence factors, may contribute to the pathogenesis of invasive GAS infections.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular Epidemiology ofngaand NAD Glycohydrolase/ADP‐Ribosyltransferase Activity amongStreptococcus pyogenesCausing Streptococcal Toxic Shock Syndrome

Stevens

Salmi²,

McIndoo³

et al. 2000

J INFECT DIS

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“…To overcome the shortage of low cell accessibility, protein delivery systems on the basis of bacterial toxins ( , ) or short peptides have been used (). We studied the cellular effects of rWTC3cer by means of a protein delivery system, which is based on the binary C. botulinum C2 toxin, which consists of the enzyme component C2I and the binding/translocation component C2II ( − ). A fusion protein was constructed consisting of the N-terminal part (amino acids 1−225) of C2I and the complete C3cer.…”

Section: Discussionmentioning

confidence: 99%

Rho-Specific Bacillus cereus ADP-Ribosyltransferase C3cer Cloning and Characterization

2003

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C3-like ADP-ribosyltransferases represent an expanding family of related exoenzymes, which are produced by Clostridia and various Staphylococcus aureus strains. Here we report on the cloning and biochemical characterization of an ADP-ribosyltransferase from Bacillus cereus strain 2339. The transferase encompasses 219 amino acids; it has a predicted mass of 25.2 kDa and a theoretical isoelectric point of 9.3. To indicate the relationship to the family of C3-like ADP-ribosyltransferases, we termed the enzyme C3cer. The amino acid sequence of C3cer is 30 to 40% identical to other C3-like exoenzymes. By site-directed mutagenesis, Arg(59), Arg(97), Tyr(151), Arg(155), Thr(178), Tyr(180), Gln(183), and Glu(185) of recombinant C3cer were identified as pivotal residues of enzyme activity and/or protein substrate recognition. Precipitation experiments with immobilized RhoA revealed that C3cerTyr(180), which is located in the so-called "ADP-ribosylating toxin turn-turn" (ARTT) motif, plays a major role in the recognition of RhoA. Like other C3-like exoenzymes, C3cer ADP-ribosylates preferentially RhoA and RhoB and to a much lesser extent RhoC. Because the cellular accessibility of recombinant C3cer is low, a fusion toxin (C2IN-C3cer), consisting of the N-terminal 225 amino acid residues of the enzyme component of C2 toxin from Clostridium botulinum and C3cer was used to study the cytotoxic effects of the transferase. This fusion toxin caused rounding up of Vero cells comparable to the effects of Rho-inactivating toxins.

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Large clostridial cytotoxins

Just

Gerhard

Reviews of Physiology, Biochemistry and Pharmacology

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203

233

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The large clostridial cytotoxins are a family of structurally and functionally related exotoxins from Clostridium difficile (toxins A and B), C. sordellii (lethal and hemorrhagic toxin) and C. novyi (alpha-toxin). The exotoxins are major pathogenicity factors which in addition to their in vivo effects are cytotoxic to cultured cell lines causing reorganization of the cytoskeleton accompanied by morphological changes. The exotoxins are single-chain protein toxins, which are constructed of three domains: receptor-binding, translocation and catalytic domain. These domains reflect the self-mediated cell entry via receptor-mediated endocytosis, translocation into the cytoplasm, and execution of their cytotoxic activity by an inherent enzyme activity. Enzymatically, the toxins catalyze the transfer of a glucosyl moiety from UDP-glucose to the intracellular target proteins which are the Rho and Ras GTPases. The covalent attachment of the glucose moiety to a conserved threonine within the effector region of the GTPases renders the Rho-GTPases functionally inactive. Whereas the molecular mode of cytotoxic effects is fully understood, the mechanisms leading to inflammatory processes in the context of disease (e.g., antibiotic-associated pseudomembranous colitis caused by Clostridium difficile) are less clear.

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Actin‐ADP‐Ribosylating Toxins: Cytotoxic Mechanisms ofClostridium botulinumC2 Toxin andClostridium perfringenslota Toxin

Cited by 4 publications

References 38 publications

Molecular Epidemiology ofngaand NAD Glycohydrolase/ADP‐Ribosyltransferase Activity amongStreptococcus pyogenesCausing Streptococcal Toxic Shock Syndrome

Molecular Epidemiology ofngaand NAD Glycohydrolase/ADP‐Ribosyltransferase Activity amongStreptococcus pyogenesCausing Streptococcal Toxic Shock Syndrome

Rho-Specific Bacillus cereus ADP-Ribosyltransferase C3cer Cloning and Characterization

Large clostridial cytotoxins

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