Tetanus neurotoxin: conformational plasticity as an adaptive strategy

Abstract

Tetanus neurotoxin (TeNT) secreted by Clostridium tetani is the causative agent of the spastic paralysis distinctive of human tetanus. TeNT is structurally related to the family of botulinum neurotoxins (BoNTs) produced by Clostridium botulinum that cause flaccid paralysis by disabling synaptic exocytosis at peripheral cholinergic neurons. By contrast, TeNT 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 TeNT domains in the context of the holotoxin in response to environmental pH, a key factor modulating TeNT 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 TeNT from its entry in the peripheral nervous system (PNS) to its ultimate site of action on central glycinergic synapses.

Tetanus and tetanus neurotoxin: From peripheral uptake to central nervous tissue targets

“…This more compact form is characterized by the HCC and the L domains interacting with each other. This conformational flexibility may be required by TeNT to perform its long molecular journey from the general circulation to the final destination inside the cytosol of inhibitory interneurons of the spinal cord (Masuyer et al., 2017; Montal, 2017).…”

A novel single-domain antibody multimer that potently neutralizes tetanus neurotoxin

“…The orientation of T6T16A12 when bound to TeNT, or the presence of either linkers or the A12 VHH increases the covered surface area likely encompassing the 2 ganglioside binding sites [21] , [22] . However, other mechanisms can also explain the increased potency of T6T16A12 such as TeNT aggregation, similar to antibody neutralization of other toxins [33] , [53] , [54] , [55] , or conformational changes [56] due to binding [15] , [25] . Elucidation of the exact binding sites of the monomers would support the rational design of additional VHH multimers covering multiple (functional) domains, as recently shown for BoNT [57] .…”