Resolution of Two Steps in Botulinum Neurotoxin Serotype A1 Light Chain Localization to the Intracellular Plasma Membrane. Int J Mol Sci 2021 Oct 15;22(20)
Date
10/24/2021Pubmed ID
34681775Pubmed Central ID
PMC8539409DOI
10.3390/ijms222011115Scopus ID
2-s2.0-85116984877 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
Botulinum neurotoxin serotype A (BoNT/A) is the most potent protein toxin to humans. BoNT/A light chain (LC/A) cleavage of the membrane-bound SNAP-25 has been well-characterized, but how LC/A traffics to the plasma membrane to target SNAP-25 is unknown. Of the eight BoNT/A subtypes (A1-A8), LC/A3 has a unique short duration of action and low potency that correlate to the intracellular steady state of LC/A, where LC/A1 is associated with the plasma membrane and LC/A3 is present in the cytosol. Steady-state and live imaging of LC/A3-A1 chimeras identified a two-step process where the LC/A N terminus bound intracellular vesicles, which facilitated an internal α-helical-rich domain to mediate LC/A plasma membrane association. The propensity of LC/A variants for membrane association correlated with enhanced BoNT/A potency. Understanding the basis for light chain intracellular localization provides insight to mechanisms underlying BoNT/A potency, which can be extended to applications as a human therapy.
Author List
Gardner A, Tepp WH, Bradshaw M, Barbieri JT, Pellett SAuthor
Joseph T. Barbieri PhD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBotulinum Toxins, Type A
Cell Membrane
Female
Humans
Intracellular Membranes
Mice
Mice, Inbred ICR
Protein Binding
Synaptosomal-Associated Protein 25
Tumor Cells, Cultured
