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Crystal structure of the catalytic domain of botulinum neurotoxin subtype A3.

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Leka O, Wu Y, Li X, Kammerer RA
OpenAccess logo J Biol Chem 296 100684
Cited: 4 times
EuropePMC logo PMID: 33891946

Abstract

Botulinum neurotoxins (BoNTs) are among the most widely used therapeutic proteins; however, only two subtypes within the seven serotypes, BoNT/A1 and BoNT/B1, are currently used for medical and cosmetic applications. Distinct catalytic properties, substrate specificities, and duration of enzymatic activities potentially make other subtypes very attractive candidates to outperform conventional BoNTs in particular therapeutic applications. For example, BoNT/A3 has a significantly shorter duration of action than other BoNT/A subtypes. Notably, BoNT/A3 is the subtype with the least conserved catalytic domain among BoNT/A subtypes. This suggests that the sequence differences, many of which concern the α-exosite, contribute to the observed functional differences in toxin persistence by affecting the binding of the substrate SNAP-25 and/or the stability of the catalytic domain fold. To identify the molecular determinants accounting for the differences in the persistence observed for BoNT/A subtypes, we determined the crystal structure of the catalytic domain of BoNT/A3 (LC/A3). The structure of LC/A3 was found to be very similar to that of LC/A1, suggesting that the overall mode of SNAP-25 binding is common between these two proteins. However, circular dichroism (CD) thermal unfolding experiments demonstrated that LC/A3 is significantly less stable than LC/A1, implying that this might contribute to the reduced toxin persistence of BoNT/A3. These findings could be of interest in developing next-generation therapeutic toxins.

Articles - 7dvl mentioned but not cited (3)

  1. Resolution of Two Steps in Botulinum Neurotoxin Serotype A1 Light Chain Localization to the Intracellular Plasma Membrane. Gardner A, Tepp WH, Bradshaw M, Barbieri JT, Pellett S. Int J Mol Sci 22 11115 (2021)
  2. Crystal structure of the catalytic domain of botulinum neurotoxin subtype A3. Leka O, Wu Y, Li X, Kammerer RA. J Biol Chem 296 100684 (2021)
  3. How Botulinum Neurotoxin Light Chain A1 Maintains Stable Association with the Intracellular Neuronal Plasma Membrane. Gardner AP, Barbieri JT, Pellett S. Toxins (Basel) 14 814 (2022)


Articles citing this publication (1)

  1. A DARPin promotes faster onset of botulinum neurotoxin A1 action. Leka O, Wu Y, Zanetti G, Furler S, Reinberg T, Marinho J, Schaefer JV, Plückthun A, Li X, Pirazzini M, Kammerer RA. Nat Commun 14 8317 (2023)


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