A Structural Perspective of the Sequence Variability Within Botulinum Neurotoxin Subtypes A1-A4

Arndt, Joseph W.; Jacobson, Mark J.; Abola, Enrique E.; Forsyth, Charles M.; Tepp, William H.; Marks, James D.; Johnson, Eric A.; Stevens, Raymond C.

doi:10.1016/j.jmb.2006.07.040

Cited by 122 publications

(99 citation statements)

References 41 publications

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“…A2NTX shares 89% amino acid sequence homology with A1NTX, 95% in light chains, and 87% in heavy chains (6). A1 toxins but not A2NTX underwent axonal transport, and the reason is considered to be a difference in the amino acid sequences between them.…”

Section: Discussionmentioning

confidence: 99%

“…The light chain contains the endopeptidase domain, which cleaves proteins associated with intracellular vesicular transport, such as SNAP-25 (synaptosomal-associated protein of 25 kDa) for type A toxin, and consequently inhibits acetylcholine release from neurons, leading to paralysis. Type A organisms have been classified into five subtypes (A1 -A5) based on the amino acid sequence variability of the produced NTX (6,7). Botulinum toxin type A products, which are used as a treatment for neurologic disorder, are produced from LL toxin or NTX derived from subtype A1 organisms (8).…”

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confidence: 99%

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Type A1 but Not Type A2 Botulinum Toxin Decreases the Grip Strength of the Contralateral Foreleg Through Axonal Transport From the Toxin-Treated Foreleg of Rats

et al. 2011

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Type A1 but Not Type A2 Botulinum Toxin Decreases the Grip Strength of the Contralateral Foreleg Through Axonal Transport From the Toxin-Treated Foreleg of Rats

et al. 2011

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“…Human botulism is generally associated with exposures to BoNTs of the serotypes A, B, E, and F. In addition to distinct serotypes, many BoNT subtypes have been recently identified based on their sequence variations and antigenic differences. [4][5][6] For example, gene sequence analysis has identified five BoNT/A subtypes (A1 through A5). [7][8][9] Whereas the sequence similarity among different serotypes is relatively low, the subtypes within a BoNT serotype generally exhibit high sequence similarity.…”

Section: Introductionmentioning

confidence: 99%

Subtyping Botulinum Neurotoxins by Sequential Multiple Endoproteases In-Gel Digestion Coupled with Mass Spectrometry

Wang¹,

Baudys²,

Rees³

et al. 2012

Anal. Chem.

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Botulinum neurotoxin (BoNT) is one of the most toxic substances known. BoNT is classified into seven distinct serotypes labeled A through G. Among individual serotypes, researchers have identified subtypes based on amino acid variability within a serotype and toxin variants with minor amino acid sequence differences within a subtype. BoNT subtype identification is valuable for tracing and tracking bacterial pathogens. A proteomics approach is useful for BoNT subtyping since botulism is caused by botulinum neurotoxin and does not require the presence of the bacteria or its DNA. Enzymatic digestion and peptide identification using tandem mass spectrometry determines toxin protein sequences. But with the conventional one-step digestion method, producing sufficient numbers of detectable peptides to cover the entire protein sequence is difficult and incomplete sequence coverage results in uncertainty in distinguishing BoNT subtypes and toxin variants because of high sequence similarity. We report here a method of multiple enzymes and sequential in-gel digestion (MESID) to characterize the BoNT protein sequence. Complementary peptide detection from toxin digestions has yielded near-complete sequence coverage for all seven BoNT serotypes. Application of the method to a BoNT-contaminated carrot juice sample resulted in the identification of 98.4% protein sequence which led to a confident determination of the toxin subtype.

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“…Having been described only recently, little is known about the A6 and A7 subtypes, and they have yet to be purified as 150-kDa holotoxins. Amino acid similarity between BoNT/A subtypes ranges from 98% (A1 versus A5) to 84% (A1 versus A3) (19). It remains unclear how these amino acid differences affect the subtypes' biologic activity, and only a few differences in characteristics have been elucidated.…”

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confidence: 99%

Characterization of Botulinum Neurotoxin A Subtypes 1 Through 5 by Investigation of Activities in Mice, in Neuronal Cell Cultures, and In Vitro

et al. 2013

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Botulinum neurotoxins (BoNTs) are synthesized by Clostridium botulinum and exist as seven immunologically distinct serotypes designated A through G. For most serotypes, several subtypes have now been described based on nominal differences in the amino acid sequences. BoNT/A1 is the most well-characterized subtype of the BoNT/A serotype, and many of its properties, including its potency, its prevalence as a food poison, and its utility as a pharmaceutical, have been thoroughly studied. In contrast, much remains unknown of the other BoNT/A subtypes. In this study, BoNT/A subtype 1 (BoNT/A1) to BoNT/A5 were characterized utilizing a mouse bioassay, an in vitro cleavage assay, and several neuronal cell-based assays. The data indicate that BoNT/A1 to -5 have distinct in vitro and in vivo toxicological properties and that, unlike those for BoNT/A1, the neuronal and mouse results for BoNT/A2 to -5 do not correlate with their enzymatic activity. These results indicate that BoNT/A1 to -5 have distinct characteristics, which are of importance for a greater understanding of botulism and for pharmaceutical applications.

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A Structural Perspective of the Sequence Variability Within Botulinum Neurotoxin Subtypes A1-A4

Cited by 122 publications

References 41 publications

Type A1 but Not Type A2 Botulinum Toxin Decreases the Grip Strength of the Contralateral Foreleg Through Axonal Transport From the Toxin-Treated Foreleg of Rats

Type A1 but Not Type A2 Botulinum Toxin Decreases the Grip Strength of the Contralateral Foreleg Through Axonal Transport From the Toxin-Treated Foreleg of Rats

Subtyping Botulinum Neurotoxins by Sequential Multiple Endoproteases In-Gel Digestion Coupled with Mass Spectrometry

Characterization of Botulinum Neurotoxin A Subtypes 1 Through 5 by Investigation of Activities in Mice, in Neuronal Cell Cultures, and In Vitro

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