The structure of the tetanus toxin reveals pH‐mediated domain dynamics

Abstract

The tetanus neurotoxin (TeNT) is a highly potent toxin produced by that inhibits neurotransmission of inhibitory interneurons, causing spastic paralysis in the tetanus disease. TeNT differs from the other clostridial neurotoxins by its unique ability to target the central nervous system by retrograde axonal transport. The crystal structure of the tetanus toxin reveals a "closed" domain arrangement stabilised by two disulphide bridges, and the molecular details of the toxin's interaction with its polysaccharide receptor. An integrative analysis combining X-ray crystallography, solution scattering and single particle electron cryo-microscopy reveals pH-mediated domain rearrangements that may give TeNT the ability to adapt to the multiple environments encountered during intoxication, and facilitate binding to distinct receptors.

The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs

“…The structure of TeNT has been resolved only recently, and it shows the typical three domains BoNT structure (Figure ) consisting of the 50‐kDa L domain endowed with a Zn 2+ ‐dependent metalloprotease activity, the HN domain (50 kDa, N‐terminal half of the H chain), and the HC domain (50 kDa, C‐terminal half of the H chain; Masuyer et al, ). TeNT is produced as a single polypeptide chain of 150 kDa with two disulfide bonds: one, conserved in BoNTs, links Cys439 to Cys467 and connects the L and HN domains; the other one joins Cys869 and Cys1093 and forms an intrachain disulfide bridge internal to the HC domain, which is unique of TeNT (Masuyer et al, ).…”

“…Crystallographic structure of tetanus neurotoxins. The picture is modified from Masuyer, Conrad, and Stenmark (). The L domain is in pink, the HN domain in yellow, and the HC domain in green.…”

“…These neurotoxins are structurally closely similar to TeNT and are produced by different bacteria, mainly Clostridia (botulinum, butyrricum, FIGURE 1 Crystallographic structure of tetanus neurotoxins. The picture is modified from Masuyer, Conrad, and Stenmark (2017). The L domain is in pink, the HN domain in yellow, and the HC domain in green.…”

Tetanus neurotoxin: conformational plasticity as an adaptive strategy

“…However, the study by Masuyer et al also raises a number of questions. Concerning the crystal structure, the pH in the actual crystal is unknown.…”

“…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.…”