Tetanus Neurotoxin (TeNT) Traffics from PNS to CNS: Molecular Structure of the TeNT Receptor Binding Domain

Abstract

The World Health Organization reported that in 2017 almost 31,000 newborns died from exposure to tetanus neurotoxin (TeNT), which is produced by the bacterium Clostridium tetani, despite there being an effective vaccine available. When an individual is exposed to TeNT, the toxin travels through the bloodstream to the peripheral nervous system (PNS) where it is trafficked to the central nervous system (CNS). TeNT cleaves vesicle‐associated membrane protein‐2 (VAMP2), a membrane protein in the CNS, blocking the release of neurotransmitters which signal muscle cells to relax, thus resulting in spastic paralysis. TeNT has two separate domains, A and B. The A domain is a protease and the B domain contains both an N‐terminal translocation domain (HCT/T) and a C‐terminal receptor binding domain (HCR/T). HCR/T is made up of 450 residues, arranged into six alpha helices and 33 beta sheets. HCR/T has two important carbohydrate‐binding pockets. The Arg1226‐containing “R” pocket binds sialic acid on b‐series gangliosides (i.e. GT1b), while the Trp1289‐containing “W” pocket binds to sugar groups on a‐series gangliosides (i.e. GM1a). Functioning “R” and “W” pockets are essential for TeNT toxicity. The Cedarburg High School SMART (Students Modeling A Research Topic) Team has designed a model of HCR/T using 3D printing technology to investigate TeNT structure‐function relationships. Further investigation into how TeNT moves from the PNS into the CNS can help elucidate new methods to cure or prevent tetanus, especially in newborn infants in developing countries where the mortality rate is significant.Support or Funding InformationNational Institutes of Health Clinical and Translational Science Award (NIH‐CTSA UL1RR031973)