Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX‐type gene cluster

Gustafsson, Robert; Berntsson, R.P.-A.; Martínez‐Carranza, Markel; Tekle, Geniver El; Odegrip, Richard; Johnson, Eric A.; Stenmark, Pål

doi:10.1002/1873-3468.12889

Cited by 14 publications

(23 citation statements)

References 67 publications

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“…The Gram-negative bacteria possessing orfX-p47 clusters harbored atypical orfX genes in comparison to their putative Gram-positive orthologs. Different cell envelope architecture between Gram-negative and Gram-positive bacteria and evidence of OrfX1, OrfX2, and P47 binding to lipids in vitro [13,14] may suggest a role for OrfX proteins related to the bacterial cell envelope. This hypothesis awaits further testing by studying of the localization of the OrfX proteins within the bacterial cells.…”

Section: Discussionmentioning

confidence: 99%

Looking for the X Factor in Bacterial Pathogenesis: Association of orfX-p47 Gene Clusters with Toxin Genes in Clostridial and Non-Clostridial Bacterial Species

Nowakowska

Douillard

Lindström

2019

Toxins

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The botulinum neurotoxin (BoNT) has been extensively researched over the years in regard to its structure, mode of action, and applications. Nevertheless, the biological roles of four proteins encoded from a number of BoNT gene clusters, i.e., OrfX1-3 and P47, are unknown. Here, we investigated the diversity of orfX-p47 gene clusters using in silico analytical tools. We show that the orfX-p47 cluster was not only present in the genomes of BoNT-producing bacteria but also in a substantially wider range of bacterial species across the bacterial phylogenetic tree. Remarkably, the orfX-p47 cluster was consistently located in proximity to genes coding for various toxins, suggesting that OrfX1-3 and P47 may have a conserved function related to toxinogenesis and/or pathogenesis, regardless of the toxin produced by the bacterium. Our work also led to the identification of a putative novel BoNT-like toxin gene cluster in a Bacillus isolate. This gene cluster shares striking similarities to the BoNT cluster, encoding a bont/ntnh-like gene and orfX-p47, but also differs from it markedly, displaying additional genes putatively encoding the components of a polymorphic ABC toxin complex. These findings provide novel insights into the biological roles of OrfX1, OrfX2, OrfX3, and P47 in toxinogenesis and pathogenesis of BoNT-producing and non-producing bacteria.

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Section: Discussionmentioning

confidence: 99%

Looking for the X Factor in Bacterial Pathogenesis: Association of orfX-p47 Gene Clusters with Toxin Genes in Clostridial and Non-Clostridial Bacterial Species

Nowakowska

Douillard

Lindström

2019

Toxins

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“…The structures of OrfX2 and P47 are unrelated to that of HAs and show that they belong to the tubular lipid-binding (TULIP) protein superfamily. Thereby, OrfX1 and OrfX2 have been found to bind to phosphatidylinositol [34]. In contrast to HAs, OrfX proteins and OrfX complexes have not been reported to interact with E-cadherin or to alter the intestinal epithelial barrier.…”

Section: Botulinum Complexesmentioning

confidence: 97%

“…OrfX1 has been detected in botulinum complex type E but not type F, whereas neither OrfX2 or P47 has been evidenced in both toxinotypes [32,33]. The structure of OrfX2 and P47 showed a similarity with TULIP family of proteins which are lipid-binding proteins [34].…”

Section: Botulinum Complexesmentioning

confidence: 99%

Botulinum Toxins, Diversity, Mode of Action, Epidemiology of Botulism in France

Popoff¹

2018

Botulinum Toxin

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Botulinum toxins (BoNTs) are the most potent toxins and are responsible for botulism, which is a neurological disease in man and animals. Botulism is characterized by flaccid paralysis and inhibition of secretions. BoNTs are produced by distinct clostridial species including Clostridium botulinum that consist in four physiological and genetic groups, atypical strains of C. baratii and C. butyricum. Recently, nonclostridial bacteria have been found to synthesize BoNTs. The particularity of BoNTs is to associate with nontoxic proteins to form large-size complexes that are resistant to acidic pH and protease degradation of the digestive tract. BoNTs are divided into 10 types based on neutralization by specific antisera and into more than 40 subtypes according to their sequence variations. All BoNTs retain a common core structure and mode of action, which consists in the inhibition of neurotransmitter release, notably acetylcholine. Human botulism occurs in three main forms: foodborne botulism, botulism by intestinal colonization including infant botulism, and wound botulism. In France, type B foodborne botulism is the most prevalent form, resulting from the traditional consumption of pork products such as home-made cured ham. Albeit less frequent, human botulism is still present in France including diverse types and origins.

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“…The gene clusters usually comprise an operon containing an ntnh gene and the bont gene and an additional operon containing haemagglutinin proteins or, alternatively, orfX genes, whose function remains to be determined [ 37 ]. Recent findings indicate that OrfX1 and OrfX2 bind phosphatidylinositol lipids [ 38 ]. OrfX2 and P47 have structural similarity to proteins from the tubular lipid-binding (TULIP) domain superfamily, which are often involved in lipid binding [ 38 , 39 ].…”

Section: Bont Variabilitymentioning

confidence: 99%

“…Recent findings indicate that OrfX1 and OrfX2 bind phosphatidylinositol lipids [ 38 ]. OrfX2 and P47 have structural similarity to proteins from the tubular lipid-binding (TULIP) domain superfamily, which are often involved in lipid binding [ 38 , 39 ]. The proteins may therefore have similar functions as HA proteins in the transiting of the toxin through the intestinal epithelial barrier [ 39 ].…”

Section: Bont Variabilitymentioning

confidence: 99%

Botulinum Neurotoxin Diversity from a Gene-Centered View

Benoit¹

2018

Toxins

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Botulinum neurotoxins (BoNTs) rank amongst the most potent toxins known. The factors responsible for the emergence of the many known and yet unknown BoNT variants remain elusive. It also remains unclear why anaerobic bacteria that are widely distributed in our environment and normally do not pose a threat to humans, produce such deadly toxins. Even the possibility of accidental toxicity to humans has not been excluded. Here, I review the notion that BoNTs may have specifically evolved to target vertebrates. Considering the extremely complex molecular architecture of the toxins, which enables them to reach the bloodstream, to recognize and enter neurons, and to block neurotransmitter release, it seems highly unlikely that BoNT toxicity to vertebrates is a coincidence. The carcass–maggot cycle provides a plausible explanation for a natural role of the toxins: to enable mass reproduction of bacteria, spores, and toxins, using toxin-unaffected invertebrates, such as fly maggots, as the vectors. There is no clear correlation between toxigenicity and a selective advantage of clostridia in their natural habitat. Possibly, non-toxigenic strains profit from carcasses resulting from the action of toxigenic strains. Alternatively, a gene-centered view of toxin evolution would also explain this observation. Toxin-coding mobile genetic elements may have evolved as selfish genes, promoting their own propagation, similar to commensal viruses, using clostridia and other bacteria as the host. Research addressing the role of BoNTs in nature and the origin of toxin variability goes hand in hand with the identification of new toxin variants and the design of improved toxin variants for medical applications. These research directions may also reveal yet unknown natural antidotes against these extremely potent neurotoxins.

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Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX‐type gene cluster

Cited by 14 publications

References 67 publications

Looking for the X Factor in Bacterial Pathogenesis: Association of orfX-p47 Gene Clusters with Toxin Genes in Clostridial and Non-Clostridial Bacterial Species

Looking for the X Factor in Bacterial Pathogenesis: Association of orfX-p47 Gene Clusters with Toxin Genes in Clostridial and Non-Clostridial Bacterial Species

Botulinum Toxins, Diversity, Mode of Action, Epidemiology of Botulism in France

Botulinum Neurotoxin Diversity from a Gene-Centered View

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