Tetanus neurotoxin: conformational plasticity as an adaptive strategy

Abstract

Tetanus neurotoxin (Te NT ) secreted by Clostridium tetani is the causative agent of the spastic paralysis distinctive of human tetanus. Te NT is structurally related to the family of botulinum neurotoxins (Bo NT s) produced by Clostridium botulinum that cause flaccid paralysis by disabling synaptic exocytosis at peripheral cholinergic neurons. By contrast, Te NT targets the central nervous system ( CNS ) by hijacking receptors for neurotrophic factors to enter peripheral neurons thereby being sorted into non‐acidifying endosomes, trafficking via retrograde axonal transport organelles, and entering spinal inhibitory interneurons after transcytosis (Fig A). In this issue of EMBO Reports , Masuyer et al describe the structural plasticity of individual Te NT domains in the context of the holotoxin in response to environmental pH , a key factor modulating Te NT fate and action. Through the concerted use of X‐ray crystallography, single particle cryo‐ EM , and small angle X‐ray scattering ( SAXS ), the authors provide snapshots of conformational transitions that may underlie the productive path of Te NT from its entry in the peripheral nervous system ( PNS ) to its ultimate site of action on central glycinergic synapses.