Crystal structure of the catalytic domain of the <i>Weissella oryzae</i> botulinum‐like toxin

Košenina, Sara; Masuyer, Geoffrey; Zhang, Sicai; Dong, Min; Stenmark, Pål

doi:10.1002/1873-3468.13446

Cited by 9 publications

(13 citation statements)

References 34 publications

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“…The LC of BoNT/Wo is a catalytically active zinc‐dependent metalloprotease previously reported to cleave the SNARE protein VAMP2 [37] and we have previously determined its crystal structure [40]. In contrast to X‐ray crystallography, it is more difficult to precisely locate protein‐bound metal ions at a moderate resolution using cryo‐EM, where images are generated based on bright‐field phase contrast, being less sensitive to atomic number [48].…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, genes for HA or OrfX proteins are missing [11,12]. So far, the only available structural information about BoNT/Wo is the crystal structure of the LC [40]. BoNT/Wo is evolutionarily distinct from all the other toxins and even from the other BoNT‐like toxins BoNT/X, BoNT/En and PMP1 that form their own evolutionary branch [8–10].…”

Section: Introductionmentioning

confidence: 99%

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The cryo‐EM structure of the BoNT/Wo‐NTNH complex reveals two immunoglobulin‐like domains

Košenina,

Škerlová,

Zhang

et al. 2023

The FEBS Journal

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The botulinum neurotoxin‐like toxin from Weissella oryzae (BoNT/Wo) is one of the BoNT‐like toxins recently identified outside of the Clostridium genus. We show that, like the canonical BoNTs, BoNT/Wo forms a complex with its non‐toxic non‐hemagglutinin (NTNH) partner, which in traditional BoNT serotypes protects the toxin from proteases and the acidic environment of the hosts' guts. We here report the cryo‐EM structure of the 300 kDa BoNT/Wo‐NTNH/Wo complex together with pH stability studies of the complex. The structure reveals molecular details of the toxin's interactions with its protective partner. The overall structural arrangement is similar to other reported BoNT‐NTNH complexes, but NTNH/Wo uniquely contains two extra bacterial immunoglobulin‐like (Big) domains on the C‐terminus. Although the function of these Big domains is unknown, they are structurally most similar to bacterial proteins involved in adhesion to host cells. In addition, the BoNT/Wo protease domain contains an internal disulfide bond not seen in other BoNTs. Mass photometry analysis revealed that the BoNT/Wo‐NTNH/Wo complex is stable under acidic conditions and may dissociate at neutral to basic pH. These findings established that BoNT/Wo‐NTNH/Wo shares the general fold of canonical BoNT–NTNH complexes. The presence of unique structural features suggests that it may have an alternative mode of activation, translocation and recognition of host cells, raising interesting questions about the activity and the mechanism of action of BoNT/Wo as well as about its target environment, receptors and substrates.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The cryo‐EM structure of the BoNT/Wo‐NTNH complex reveals two immunoglobulin‐like domains

Košenina,

Škerlová,

Zhang

et al. 2023

The FEBS Journal

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“…In addition, BoNT/like sequences have been identified in non-clostridial species such as Weissella oryzae , Enterococcus faecium and Chryseobacterium piperi [16] as well as a new BoNT serotype, tentatively named BoNT/X found in the Clostridium Botulinum strain 111 [17]. BoNT/Wo from W. oryzae adds to the BoNT diversity as a recognized novel toxinotype that cleaves VAMP2 similarly to BoNT/B, D, F and G [17,18,19]). The neurotoxin gene cluster recently identified within E. faecium encodes for a novel putative eBoNT/J (also called BoNT/En) but more importantly, the public health implications and potential therapeutic use of the novel BoNT types remain to be defined [20].…”

Section: Diversity and Structure Of Bontsmentioning

confidence: 99%

Antibodies and Vaccines against Botulinum Toxins: Available Measures and Novel Approaches

Rasetti-Escargueil

Popoff

2019

Toxins

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Botulinum neurotoxin (BoNT) is produced by the anaerobic, Gram-positive bacterium Clostridium botulinum. As one of the most poisonous toxins known and a potential bioterrosism agent, BoNT is characterized by a complex mode of action comprising: internalization, translocation and proteolytic cleavage of a substrate, which inhibits synaptic exocytotic transmitter release at neuro-muscular nerve endings leading to peripheral neuroparalysis of the skeletal and autonomic nervous systems. There are seven major serologically distinct toxinotypes (A–G) of BoNT which act on different substrates. Human botulism is generally caused by BoNT/A, B and E. Due to its extreme lethality and potential use as biological weapon, botulism remains a global public health concern. Vaccination against BoNT, although an effective strategy, remains undesirable due to the growing expectation around therapeutic use of BoNTs in various pathological conditions. This review focuses on the current approaches for botulism control by immunotherapy, highlighting the future challenges while the molecular underpinnings among subtypes variants and BoNT sequences found in non-clostridial species remain to be elucidated.

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“…A total of seven serotypes [ 7 ] (BoNT/A to /G) have been identified as well as a novel serotype (BoNT/X) that is not neutralised by any known BoNT antibody [ 8 , 9 ]. Advancements in genome sequencing have also led to the discovery of mosaic BoNTs (BoNT/FA(HA), /CD, and /DC) [ 10 , 11 , 12 , 13 ] as well as BoNT-like proteins from Weissella oryzae (‘BoNT/Wo’) [ 14 , 15 , 16 ], Enterococcus faecium (‘BoNT/En’) [ 17 , 18 ], and Paraclostridium bifermentans (‘PMP1’) [ 19 ]. Toxicity across serotypes varies significantly, with BoNT/A, /B, /E, and /F associated with human disease [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

A Comprehensive Structural Analysis of Clostridium botulinum Neurotoxin A Cell-Binding Domain from Different Subtypes

Gregory

Acharya

2023

Toxins

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Botulinum neurotoxins (BoNTs) cause flaccid neuromuscular paralysis by cleaving one of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex proteins. BoNTs display high affinity and specificity for neuromuscular junctions, making them one of the most potent neurotoxins known to date. There are seven serologically distinct BoNTs (serotypes BoNT/A to BoNT/G) which can be further divided into subtypes (e.g., BoNT/A1, BoNT/A2…) based on small changes in their amino acid sequence. Of these, BoNT/A1 and BoNT/B1 have been utilised to treat various diseases associated with spasticity and hypersecretion. There are potentially many more BoNT variants with differing toxicological profiles that may display other therapeutic benefits. This review is focused on the structural analysis of the cell-binding domain from BoNT/A1 to BoNT/A6 subtypes (HC/A1 to HC/A6), including features such as a ganglioside binding site (GBS), a dynamic loop, a synaptic vesicle glycoprotein 2 (SV2) binding site, a possible Lys–Cys/Cys–Cys bridge, and a hinge motion between the HCN and HCC subdomains. Characterising structural features across subtypes provides a better understanding of how the cell-binding domain functions and may aid the development of novel therapeutics.

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Crystal structure of the catalytic domain of the Weissella oryzae botulinum‐like toxin

Cited by 9 publications

References 34 publications

The cryo‐EM structure of the BoNT/Wo‐NTNH complex reveals two immunoglobulin‐like domains

The cryo‐EM structure of the BoNT/Wo‐NTNH complex reveals two immunoglobulin‐like domains

Antibodies and Vaccines against Botulinum Toxins: Available Measures and Novel Approaches

A Comprehensive Structural Analysis of Clostridium botulinum Neurotoxin A Cell-Binding Domain from Different Subtypes

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