Conformational space of the translocation domain
Résumé
The botulinum neurotoxins (BoNTs), among the most powerful toxic compounds found in nature, are formed of various domains [1]. The underlying toxicity mechanism is based on a sequence of molecular events, in particular the translocation of the catalytic domain through the membrane of a neurotransmitter vesicle into the cytosol of the neuron. A recent structural study [2] of the isolated translocation domain of BoNT suggests a model for the interaction of this domain with the membrane, based on the transition of the α helical switch towards a β hairpin. The present work investigates this proposition and the consequences for the interaction between toxin and membrane using atomistic simulations in conjunction with the mesoscopic Twister model [3]. The various conformational mobilities of the translocation domain observed according to the starting conformation, protonation and solvent type, as well as the effect of the membrane examined in an implicit way by comparing water and water-ethanol solvents leads to the conclusion that the protruding switch hairpin is essential for the interaction between the protein and the membrane and that its appearance modifies the internal dynamics and the effect of hydrophobicity on the whole protein. In addition, the central two α helices, helix1 and helix2, forming two coiled-coil motifs, are analyzed in the framework of the Twister model, in which the deformation of the membrane by the protein is caused by the presence of local torques due to the asymmetry of the hydrophobic residues on helices. Different torque distributions are observed depending on the α or β conformation of the switch and permit to propose an origin for the mechanism opening the membrane.
References
[1] G. Cottone, L. Chiodo, L. Maragliano, M. R. Popoff, C. Rasetti-Escargueil, E. Lemichez, and T. E. Malliavin. In Silico Conformational Features of Botulinum Toxins A1 and E1 According to Intraluminal Acidification. Toxins (Basel) (2022), 14(9).
[2] K. H. Lam, Z. Guo, N. Krez, T. Matsui, K. Perry, J. Weisemann, A. Rummel, M. E. Bowen, and R.Jin. A viral-fusion-peptide-like molecular switch drives membrane insertion of botulinum neurotoxin A1. Nat Commun (2018), 9:5367.
[3] J. Fierling, A. Johner, I. M. Kulic,́ H. Mohrbach, and M. M. Muller. How bio-filaments twist
membranes. Soft Matter (2016), 12(26):5747-5757.
Origine : Fichiers produits par l'(les) auteur(s)