Abstract
The clostridial neurotoxins (CNTs), botulinum toxin and tetanus toxin, are the most toxic proteins for humans. Neurotoxicity is based upon the specificity of the CNTs for neural host receptors and substrates. CNTs are organized into three domains, a Light Chain (LC) that is a metalloprotease and a Heavy Chain (HC) that has two domains, an N-terminal LC translocation domain (HCN) and a C-terminal receptor binding domain (HCC). While catalysis and receptor binding functions of the CNTs have been developed, our understanding of LC translocation is limited. This is due to the intrinsic complexity of the translocation process and limited tools to assess the step-by-step events in LC translocation. Recently, we developed a novel, cell-based TT-reporter to measure LC translocation as the translocation of a β-lactamase reporter across a vesicle membrane in neurons. Using this approach, we identified a role for a cis-Loop, located within the HCN, in LC translocation. In this commentary, we describe our current understanding of how CNTs mediate LC translocation and place the role of the cis-Loop in the LC translocation process relative to other independent functions that have been implicated in LC translocation. Understanding the basis for LC translocation will enhance the use of CNTs in vaccine development and as human therapies.
Highlights
The clostridial neurotoxins, tetanus toxin and the botulinum toxinsDue to use as human vaccines and therapies, the clostridial neurotoxins (CNTs) have been subjected to decades of scientific investigation using biophysical, electrophysiological, and pharmacological approaches to establish mechanisms of toxin action
“Tetanus toxin cis-Loop contributes to LightChain translocation,” by Zuverink et al [1], identified a structurally conserved, charged loop that upon aliphatic mutation uncoupled Light Chain (LC) translocation, but not pore-formation
Dichain CNTs are covalently linked through an interchain disulfide composed of the N-terminal Light Chain (LC) and C-terminal Heavy Chain (HC)
Summary
Due to use as human vaccines and therapies, the clostridial neurotoxins (CNTs) have been subjected to decades of scientific investigation using biophysical, electrophysiological, and pharmacological approaches to establish mechanisms of toxin action. While progress has been made towards resolving the catalytic and host receptor mechanisms, and several conserved structures are implicated in the translocation process, the discrete steps in the translocation process remain cloak-and-dagger. “Tetanus toxin cis-Loop contributes to LightChain translocation,” by Zuverink et al [1], identified a structurally conserved, charged loop (termed cis-Loop) that upon aliphatic mutation uncoupled LC translocation, but not pore-formation. In this commentary, we discuss potential functions of the cis-Loop by examining proteins containing similar secondary structural elements together with current translocation models. A deeper understanding of structure-function properties of LC translocation will facilitate identification of structural motifs in emerging bacterial toxins that can be targeted for the intracellular neutralization of toxin action
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