Toxicon, Journal Year: 2024, Volume and Issue: 237, P. 107463 - 107463
Published: Jan. 1, 2024
Language: Английский
Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)
Published: Dec. 18, 2023
In this study, we characterize Designed Ankyrin Repeat Proteins (DARPins) as investigative tools to probe botulinum neurotoxin A1 (BoNT/A1) structure and function. We identify DARPin-F5 that completely blocks SNAP25 substrate cleavage by BoNT/A1 in vitro. X-ray crystallography reveals inhibits activity interacting with a substrate-binding region between the α- β-exosite. This DARPin does not block of BoNT/A3, indicating is subtype-specific inhibitor. Glu-171 plays critical role interaction its mutation Asp, residue found results loss inhibition cleavage. contrast vitro results, promotes faster primary neurons muscle tissue increasing toxin translocation. Our findings could have important implications for application therapeutic areas requiring onset action combined long persistence.
Language: Английский
Citations
3
Toxins, Journal Year: 2022, Volume and Issue: 14(10), P. 708 - 708
Published: Oct. 15, 2022
Excess sebum (seborrhea) results in oily skin and is associated with large pore size acne. Studies healthy, seborrheic volunteers have reported that intradermal injection of commercial preparations botulinum neurotoxin type A (BoNT/A) (onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA) reduced production, thus, oiliness size. The mechanism for these effects has not been fully elucidated; however, several theories involving direct or indirect BoNT/A on neuronal and/or dermal cells (e.g., sebocytes) proposed. In the present study, we evaluated effect native research grade complex, a preparation (onabotA), variants sebocyte lipogenesis using an vitro cell model. We show picomolar concentrations (BoNT/A complex: half maximal effective concentration [EC50] = 24 pM; 150 kDa: EC50 34 pM) modulate reduce oleic acid-induced differentiation, lipogenesis, holocrine-like secretion. Comparative studies binding domain BoNT/A, which lacks enzymatic activity, this independent activity likely occurs via surface receptors fibroblast growth factor receptors). Overall, shed light potential action rationale use treatment sebum-related conditions.
Language: Английский
Citations
5
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown
Published: Feb. 4, 2023
Abstract Tetanus toxin is one of the most potent neurotoxins and causative agent tetanus. This neurotoxin binds to neuromuscular junction and, after internalisation into motor neurons, undergoes long-distance axonal transport transcytosis spinal cord inhibitory interneurons. Inside cytoplasm interneurons, catalytic chain blocks neurotransmitter release, leading spastic paralysis. Whilst effects tetanus intoxication have been extensively studied, molecular composition its receptor complex still poorly understood. We previously shown that extracellular matrix proteins nidogens are essential for binding junction. In this study, we show tyrosine phosphatase LAR interacts with nidogen-tetanus enables uptake neurons. Binding mediated by fibronectin III domains, which harnessed inhibit entry Surprisingly, function independent role in regulating neurotrophic activity TrkB receptor, has augment signalling endosomes containing neurotoxin. These findings identify a multi-subunit acting as protein neurotoxin, demonstrate novel endocytic trafficking route Our study paves way dissecting mechanisms control recognition physiological ligands pathological at neuronal plasma membrane, well their targeting retrograde pathway within nervous system.
Language: Английский
Citations
2
Handbook of clinical neurology, Journal Year: 2023, Volume and Issue: unknown, P. 539 - 555
Published: Jan. 1, 2023
Language: Английский
Citations
2
Toxicon, Journal Year: 2024, Volume and Issue: 237, P. 107463 - 107463
Published: Jan. 1, 2024
Language: Английский
Citations
0