Assembly and Function of the Botulinum Neurotoxin Progenitor Complex

Gu, Shenyan; Jin, Rongsheng

doi:10.1007/978-3-662-45790-0_2

Cited by 7 publications

(6 citation statements)

References 105 publications

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“…One study compared BoNT/A, which contained such a structure, alone or in complex with nontoxic nonhemagglutinins, which are accessory proteins that lacked a crystal structure. The epitopes predominantly mapped to LC and HC N when BoNT/A was in complex, which is in agreement with current models of the BoNT complex (36,37), which have shown the HC C to be shielded. The isolated translocation domain of the botulinum neurotoxin subunit also contains multiple epitopes, demonstrating the potential for multiple mechanisms of neutralization (35).…”

Section: T His Commentary Addresses Studies By Mantis and Coworkers supporting

confidence: 90%

Protein Structure Facilitates High-Resolution Immunological Mapping

Zuverink

Barbieri

2017

Clin Vaccine Immunol

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Select agents (SA) pose unique challenges for licensing vaccines and therapies. In the case of toxin-mediated diseases, HHS assigns guidelines for SA use, oversees vaccine and therapy development, and approves animal models and approaches to identify mechanisms for toxin neutralization. In this commentary, we discuss next-generation vaccines and therapies against ricin toxin and botulinum toxin, which are regulated SA toxins that utilize structure-based approaches for countermeasures to guide rapid response to future biothreats.KEYWORDS botulinum toxin, RTA, RVEc, RiVax, antibodies, mass spectrometry, ricin T his commentary addresses studies by Mantis and coworkers, who in this issue of Clinical and Vaccine Immunology describe the continued mapping of the neutralizing epitopes within ricin toxin (RTX) and relate these studies to current research on the botulinum neurotoxins (BoNTs) (1, 2). Our goal is to provide a perspective on how protein structure has facilitated development of vaccines and therapies against regulated select agent (SA) toxins. An overview of the properties of ricin toxin and botulinum neurotoxin is presented in Fig. 1. Ricin toxin and the botulinum neurotoxins are HHS and USDA Select Agents and Toxins (7 CFR part 331, 9 CFR part 121, and 42 CFR part 73).AB toxin structure/function. AB toxins contain modular domains with distinct functional activities (3). The A domain encodes an enzymatic activity which targets a host protein to modulate host cell physiology, often inactivating a biological process within cells, leading to cell death or occasionally enhancing the action of a cellular process. The B domain often binds a host receptor, such as a protein or glycolipid, via interactions that bind directly to a specific host receptor or that bind a carbohydrate present on a glycosylated host receptor. AB toxins are often synthesized as single-chain proteins in an inactive form and are converted to an active di-chain by proteolysis between the A and B domains, which remain connected by an interchain disulfide (4, 5).RTX is a category B bioterrorism toxigenic lectin enriched in seeds of the castor bean plant Ricinus communis. RTX is posttranslationally processed by host glycosylation and activated by cleavage between A and B domains (6, 7). The ricin toxin A domain (RTA) is a type II ribosome-inactivating protein with N-glycosidase activity, which depurinates 28S rRNA within the 60S host ribosome (8). Depurination stalls protein synthesis and induces a ribotoxic stress response (9). Ricin toxin B domain (RTB) contains at least two homologous lectin binding sites specific for galactose and binds galactose-containing lipids and glycoproteins (10). While binding of galactose results in nonproductive uptake of RTX, binding to mannose moieties on host mannose-containing receptors results in RTX retrograde trafficking to the endoplasmic reticulum, where RTA is delivered into the cytosol to target the ribosome (11). RTX exploits receptors on multiple cell types; therefore, the symptoms vary based ...

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Section: T His Commentary Addresses Studies By Mantis and Coworkers supporting

confidence: 90%

Protein Structure Facilitates High-Resolution Immunological Mapping

Zuverink

Barbieri

2017

Clin Vaccine Immunol

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“…Auxiliary proteins containing haemaglutinins and non-haemaglutinins participate in the stabilization of the BoNT/A complex and preservation in extracellular space and throughout the gastrointestinal tract (Chen et al, 1998;Gu and Jin, 2013;Lee et al, 2013). Figure 1 …”

Section: 1 Structure Of Bont/a Complexmentioning

confidence: 99%

Botulinum toxin A, brain and pain

Matak

Lacković

2014

Progress in Neurobiology

147

114

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“…HA34 and HA52 from botulinum complex type B seem to encase HA17, which is sensitive to protease digestion, and likely to have an important protective function [7]. HA35 and HA52 from botulinum complex type A are resistant to protease digestion, whereas NTNH/A and BoNT/A are rapidly degraded [28,33,51,161], and yet NTNH, which is structurally related to BoNT, associates with BoNT in a pH-dependent manner to form a medium-sized botulinum complex highly resistant to acidic pH and protease degradation [68,69]. Similarly, although BoNT/D and NTNH/D are individually easily degraded by pepsin or trypsin treatment, the complexes resulting from association of BoNT/D and NTNH/D are highly resistant [117].…”

Section: Experimental Botulism By Gastrointestinal Routementioning

confidence: 99%

Absorption and Transport of Botulinum Neurotoxins

Popoff

Connan

2014

Molecular Aspects of Botulinum Neurotoxin

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Botulinum neurotoxin (BoNT) is a potent toxin, which blocks the neurotransmitter release at neuromuscular junctions. BoNT can be acquired from the digestive tract (food-borne botulism, Clostridium botulinum intestinal colonization), respiratory tract (inhalational botulism), or wound (wound botulism). BoNT associates to nontoxic proteins (ANTPs), which have a main role in toxin protection against acidic pH and proteases, especially in the gastrointestinal tract. BoNT, which enters through the digestive or respiratory tract, has to first cross the epithelial barrier. This is achieved by a receptor-mediated transcytosis, which delivers the whole and active toxin at the basolateral side of epithelial cells. ANTPs containing hemagglutinins (HAs) may have an additional role in altering the intercellular junctions and facilitating toxin passage through the paracellular way. Then, BoNT disseminates locally and at distance via the blood/lymph circulation and possibly via a retrograde axonal transport to the target motor neuron endings, where the toxin uses an endocytic pathway permitting the release of the light (L)-chain into the cytosol and its subsequent proteolytic activity towards the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins involved in the neurotransmitter exocytosis.

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Assembly and Function of the Botulinum Neurotoxin Progenitor Complex

Cited by 7 publications

References 105 publications

Protein Structure Facilitates High-Resolution Immunological Mapping

Protein Structure Facilitates High-Resolution Immunological Mapping

Botulinum toxin A, brain and pain

Absorption and Transport of Botulinum Neurotoxins

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