Stealth and mimicry by deadly bacterial toxins

Yates, Susan P.; Jørgensen, René; Andersen, G.R.; Merrill, A. Rod

doi:10.1016/j.tibs.2005.12.007

Cited by 100 publications

(97 citation statements)

References 67 publications

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“…There is significant interest in the role of mono-ADP-ribosylation in human pathology, because many bacterial toxins are ARTs that disrupt cellular functions and affect human health (4,7). The number of known toxins with ART activity is growing (10)(11)(12), and the new candidates require the characterization of their cellular targets.…”

Section: Discussionmentioning

confidence: 99%

“…The mAf1521 not only binds the G protein ␤ subunit that we have shown to be modified on arginine (17) but also GDH that is modified on cysteine (18), eEF2 on diphthamide (7,31), and GRP78/BiP on an unidentified amino acid, clearly indicating that the recognition of the ADP-ribose is independent of the modified amino acid. This highlights the potential of our methodology and its relevance for the definition of the role of the ADP-ribosylation reaction.…”

Section: Purification and Identification Of Substrates Of Intracellulmentioning

confidence: 95%

“…After translocation into the host cell, they modify eukaryotic proteins with high specificity and affect their biological functions (4). Diphtheria toxin (DT), produced by Corynebacterium diphtheriae, was the first bacterial ART family member to be identified (5)(6)(7). Along with the related exotoxin A, which is produced by Pseudomonas aeruginosa, DT inhibits protein synthesis in intoxicated cells by catalyzing the ADP-ribosylation of diphthamide of elongation factor 2 (eEF2) (5)(6)(7).…”

mentioning

confidence: 99%

“…Diphtheria toxin (DT), produced by Corynebacterium diphtheriae, was the first bacterial ART family member to be identified (5)(6)(7). Along with the related exotoxin A, which is produced by Pseudomonas aeruginosa, DT inhibits protein synthesis in intoxicated cells by catalyzing the ADP-ribosylation of diphthamide of elongation factor 2 (eEF2) (5)(6)(7). Cholera toxin and pertussis toxin (PT) are two other well-characterized bacterial ARTs that are produced by Vibrio cholerae and Bordetella pertussis, respectively, and that ADP-ribosylate the ␣ subunits of the heterotrimeric G proteins (4,8,9).…”

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confidence: 99%

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Combining affinity purification by ADP-ribose-binding macro domains with mass spectrometry to define the mammalian ADP-ribosyl proteome

Dani

Stilla

Marchegiani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

104

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Mono-ADP-ribosylation is a reversible posttranslational modification that modulates the function of target proteins. The enzymes that catalyze this reaction in mammalian cells are either bacterial pathogenic toxins or endogenous cellular ADP-ribosyltransferases. For the latter, both the enzymes and their targets have largely remained elusive, mainly due to the lack of specific techniques to study this reaction. The recent discovery of the macro domain, a protein module that interacts selectively with ADP-ribose, prompted us to investigate whether this interaction can be extended to the identification of ADP-ribosylated proteins. Here, we report that macro domains can indeed be used as selective baits for high-affinity purification of mono-ADP-ribosylated proteins, which can then be identified by mass spectrometry. Using this approach, we have identified a series of cellular targets of ADP-ribosylation reactions catalyzed by cellular ADP-ribosyltransferases and toxins. These proteins include most of the known targets of ADP-ribosylation, indicating the validity of this method, and a large number of other proteins, which now need to be individually validated. This represents an important step toward the discovery of new ADP-ribosyltransferase targets and an understanding of the physiological role and the pharmacological potential of this protein modification.ADP-ribosylation ͉ ADP-ribosyltransferase ͉ NAD ͉ toxin ͉ posttranslational modification

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Section: Discussionmentioning

confidence: 99%

Section: Purification and Identification Of Substrates Of Intracellulmentioning

confidence: 95%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Combining affinity purification by ADP-ribose-binding macro domains with mass spectrometry to define the mammalian ADP-ribosyl proteome

Dani

Stilla

Marchegiani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

104

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“…These bacterial and eukaryotic protein (ADP-ribosyl)transferases (ARTs) share similar substrates (all proteins), catalytic mechanisms, and general overall 3D fold (12,13). In all cases, the ADP-ribosyl donor is NAD ϩ , and enzyme action transfers the ADP-ribose unit to a susceptible amino acid residue on the target protein with loss of nicotinamide.…”

mentioning

confidence: 99%

Rifamycin antibiotic resistance by ADP-ribosylation: Structure and diversity of Arr

Baysarowich

Koteva

Hughes

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

160

196

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The rifamycin antibiotic rifampin is important for the treatment of tuberculosis and infections caused by multidrug-resistant Staphylococcus aureus. Recent iterations of the rifampin core structure have resulted in new drugs and drug candidates for the treatment of a much broader range of infectious diseases. This expanded use of rifamycin antibiotics has the potential to select for increased resistance. One poorly characterized mechanism of resistance is through Arr enzymes that catalyze ADP-ribosylation of rifamycins. We find that genes encoding predicted Arr enzymes are widely distributed in the genomes of pathogenic and nonpathogenic bacteria. Biochemical analysis of three representative Arr enzymes from environmental and pathogenic bacterial sources shows that these have equally efficient drug resistance capacity in vitro and in vivo. The 3D structure of one of these orthologues from Mycobacterium smegmatis was determined and reveals structural homology with ADP-ribosyltransferases important in eukaryotic biology, including poly(ADP-ribose) polymerases (PARPs) and bacterial toxins, despite no significant amino acid sequence homology with these proteins. This work highlights the extent of the rifamycin resistome in microbial genera with the potential to negatively impact the expanded use of this class of antibiotic.crystallography ͉ resistome ͉ rifampin ͉ ribosyltransferase

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Cytopathology of Pathogenic Prokaryotes

Brogden

2009

Ultrastructural Pathology the Comparative Cellular Basis of Disease

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Stealth and mimicry by deadly bacterial toxins

Cited by 100 publications

References 67 publications

Combining affinity purification by ADP-ribose-binding macro domains with mass spectrometry to define the mammalian ADP-ribosyl proteome

Combining affinity purification by ADP-ribose-binding macro domains with mass spectrometry to define the mammalian ADP-ribosyl proteome

Rifamycin antibiotic resistance by ADP-ribosylation: Structure and diversity of Arr

Cytopathology of Pathogenic Prokaryotes

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