Actin-specific ADP-ribosyltransferase produced by a Clostridium difficile strain

Popoff, Michel R.; Rubín, Eric J.; Gill, D M; Boquet, Patrice

doi:10.1128/iai.56.9.2299-2306.1988

Cited by 301 publications

(129 citation statements)

References 35 publications

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“…The annual mortality attributable to CDI rose by 72% in the UK to 6500 cases in 2006 [19]. By 2005, RT 027 had been detected in an outbreak in The Netherlands [20], and by 2007 it had been isolated in 16 European countries [21,22]. The application of genotyping methods confirmed that RT 027 strains are genetically highly uniform.…”

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confidence: 90%

The Clostridium difficile PCR ribotype 027 lineage: a pathogen on the move

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Cairns

Wren

2014

Clinical Microbiology and Infection

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Clostridium difficile is a Gram-positive, spore-forming, human and animal pathogen that is the major cause of antibiotic-associated diarrhoea worldwide. The past decade has seen the rapid emergence of the hypervirulent PCR ribotype (RT) 027 complex, which has been associated with increases in the incidence and severity of disease and mortality. In this review, we describe the potential virulence factors that have been reported in strains from the RT 027 complex. We review the emergence, population structure, dissemination and evolution of this lineage.

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confidence: 90%

The Clostridium difficile PCR ribotype 027 lineage: a pathogen on the move

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Cairns

Wren

2014

Clinical Microbiology and Infection

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“…The oldest variant strains in collections known to the author are isolates from 1985 (toxinotype III, IV, XXIII). Among older variant isolates is also the first binary toxin positive strain CD196 isolated in France (Popoff et al, 1988), the first known strain of type BI/NAP1/027 in Europe.…”

Section: How Old Are Toxinotypes?mentioning

confidence: 99%

Heterogeneity of large clostridial toxins: importance ofClostridium difficiletoxinotypes

2008

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Clostridium difficile toxinotypes are groups of strains defined by changes in the PaLoc region encoding two main virulence factors: toxins TcdA and TcdB. Currently, 24 variant toxinotypes (I-XXIV) are known, in addition to toxinotype 0 strains, which contain a PaLoc identical to the reference strain VPI 10463. Variant toxinotypes can also differ from toxinotype 0 strains in their toxin production pattern. The most-studied variant strains are TcdA-, TcdB+ (A-B+) strains and binary toxin CDT-producing strains. Variations in toxin genes are also conserved on the protein level and variant toxins can differ in size, antibody reactivity, pattern of intracellular targets (small GTPases) and consequently in their effects on the cell. Toxinotypes do not correlate with particular forms of disease or patient populations, but some toxinotypes (IIIb and VIII) are currently associated with disease of increased severity and outbreaks worldwide. Variant toxinotypes are very common in animal hosts and can represent from 40% to 100% of all isolates. Among human isolates, variant toxinotypes usually represent up to 10% of strains but their prevalence is increasing.

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“…Two families can be distinguished, the iota and C2 families . Iota family encompasses iota toxin from Clostridium perfringens type E (Stiles and Wilkins, 1986), C. spiroforme toxin (ST; Popoff and Boquet, 1988a) and C. difficile ADP-ribosyltransferase (CDT) synthesized by some strains of C. difficile (Popoff et al, 1988b;Perelle et al, 1997a;Gulke et al, 2001), while the C2 family consists of C2 toxins from C. botulinum C and D (Aktories et al, 1986;Ohishi and Tsuyama, 1986). The clostridial binary toxins are related to the vegetative insecticidal proteins produced by Bacillus cereus and B. thuringiensis, which are also actin ADPribosylating toxins, and more distantly to anthrax toxins from B. anthracis Popoff and Stiles, 2006).…”

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confidence: 99%

Residues involved in the pore-forming activity of theClostridium perfringensiota toxin

et al. 2014

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SummaryClostridium perfringens iota toxin is a binary toxin that is organized into enzyme (Ia) and binding (Ib) components. Ib forms channels in lipid bilayers and mediates the transport of Ia into the target cells. Here we show that Ib residues 334-359 contain a conserved pattern of alternating hydrophobic and hydrophilic residues forming two amphipathic β-strands involved in membrane insertion and channel formation. This stretch of amino acids shows remarkable structural and functional analogies with the β-pore-forming domain of C. perfringens epsilon toxin. Several mutations within the two amphipathic β-strands affected pore formation, single-channel conductance and ion selectivity (S339E-S341E, Q345H N346E) confirming their involvement in channel formation. F454 of Ib corresponds to the Φ-clamp F427 of anthrax protective antigen and F428 of C2II binary toxins. The mutation F454A resulted in a loss of cytotoxicity and strong increase in singlechannel conductance (500 pS as compared with 85 pS in 1 M KCl) with a slight decrease in cation selectivity, indicating that the Φ-clamp is highly conserved and crucial for binary toxin activity. In contrast, the mutants Q367D, N430D, L443E had no or only minor effects on Ib properties, while T360I, T360A and T360W caused a dramatic effect on ion selectivity and single-channel conductance, indicating gross disturbance of the oligomer structure. This suggests that, at least in the iota toxin family, T360 has a structural role in the pore organization. Moreover, introduction of charged residues within the channel (S339E-S341E) or in the vestibule (Q367D, N430D and L443E) had virtually no effect on chloroquine or Ia binding, whereas F454A, T360I, T360A and T360W strongly decreased the chloroquine and Ia affinity to Ib. These results support that distinct residues within the vestibule interact with chloroquine and Ia or are responsible for channel structure, while the channel lining amino acids play a less important role.

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Actin-specific ADP-ribosyltransferase produced by a Clostridium difficile strain

Cited by 301 publications

References 35 publications

The Clostridium difficile PCR ribotype 027 lineage: a pathogen on the move

The Clostridium difficile PCR ribotype 027 lineage: a pathogen on the move

Heterogeneity of large clostridial toxins: importance ofClostridium difficiletoxinotypes

Residues involved in the pore-forming activity of theClostridium perfringensiota toxin

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