Engineering of botulinum neurotoxins as novel therapeutic tools

Dolly, J. Oliver; Wang, Jiafu

doi:10.1016/b978-0-12-800188-2.00034-3

Cited by 3 publications

(1 citation statement)

References 70 publications

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“…With the latest protein design technology, it is possible to synthesize proteins possessing a desired structure and/or a desired function [24][25][26][27]. However, it is still challenging to design transmembrane b-barrels exhibiting large conformational changes upon b-barrel formation, such as b-PFTs [28,29].…”

Section: Biochemical Characteristics Of the Mutantsmentioning

confidence: 99%

Chimeric mutants of staphylococcal hemolysin, which act as both one‐component and two‐component hemolysin, created by grafting the stem domain

et al. 2022

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Staphylococcus aureus expresses several hemolytic pore‐forming toxins (PFTs), which are all commonly composed of three domains: cap, rim and stem. PFTs are expressed as soluble monomers and assemble to form a transmembrane β‐barrel pore in the erythrocyte cell membrane. The stem domain undergoes dramatic conformational changes to form a pore. Staphylococcal PFTs are classified into two groups: one‐component α‐hemolysin (α‐HL) and two‐component γ‐hemolysin (γ‐HL). The α‐HL forms a homo‐heptamer, whereas γ‐HL is an octamer composed of F‐component (LukF) and S‐component (Hlg2). Because PFTs are used as materials for nanopore‐based sensors, knowledge of the functional properties of PFTs is used to develop new, engineered PFTs. However, it remains challenging to design PFTs with a β‐barrel pore because their formation as transmembrane protein assemblies requires large conformational changes. In the present study, aiming to investigate the design principles of the β‐barrel formed as a consequence of the conformational change, chimeric mutants composed of the cap/rim domains of α‐HL and the stem of LukF or Hlg2 were prepared. Biochemical characterization and electron microscopy showed that one of them assembles as a heptameric one‐component PFT, whereas another participates as both a heptameric one‐ and heptameric/octameric two‐component PFT. All chimeric mutants intrinsically assemble into SDS‐resistant oligomers. Based on these observations, the role of the stem domain of these PFTs is discussed. These findings provide clues for the engineering of staphylococcal PFT β‐barrels for use in further promising applications.

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Section: Biochemical Characteristics Of the Mutantsmentioning

confidence: 99%

Chimeric mutants of staphylococcal hemolysin, which act as both one‐component and two‐component hemolysin, created by grafting the stem domain

et al. 2022

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Novel Native and Engineered Botulinum Neurotoxins

Steward

Brin

Brideau-Andersen

2020

Handbook of Experimental Pharmacology

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Clostridial Binary Toxins: Basic Understandings that Include Cell Surface Binding and an Internal “Coup de Grâce”

Stiles

2016

Current Topics in Microbiology and Immunology

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Clostridium species can make a remarkable number of different protein toxins, causing many diverse diseases in humans and animals. The binary toxins of Clostridium botulinum, C. difficile, C. perfringens, and C. spiroforme are one group of enteric-acting toxins that attack the actin cytoskeleton of various cell types. These enterotoxins consist of A (enzymatic) and B (cell binding/membrane translocation) components that assemble on the targeted cell surface or in solution, forming a multimeric complex. Once translocated into the cytosol via endosomal trafficking and acidification, the A component dismantles the filamentous actin-based cytoskeleton via mono-ADP-ribosylation of globular actin. Knowledge of cell surface receptors and how these usurped, host-derived molecules facilitate intoxication can lead to novel ways of defending against these clostridial binary toxins. A molecular-based understanding of the various steps involved in toxin internalization can also unveil therapeutic intervention points that stop the intoxication process. Furthermore, using these bacterial proteins as medicinal shuttle systems into cells provides intriguing possibilities in the future. The pertinent past and state-of-the-art present, regarding clostridial binary toxins, will be evident in this chapter.

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Engineering of botulinum neurotoxins as novel therapeutic tools

Cited by 3 publications

References 70 publications

Chimeric mutants of staphylococcal hemolysin, which act as both one‐component and two‐component hemolysin, created by grafting the stem domain

Chimeric mutants of staphylococcal hemolysin, which act as both one‐component and two‐component hemolysin, created by grafting the stem domain

Novel Native and Engineered Botulinum Neurotoxins

Clostridial Binary Toxins: Basic Understandings that Include Cell Surface Binding and an Internal “Coup de Grâce”

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