Structural studies of botulinum neurotoxin progenitor complexes and tetanus neurotoxin

Abstract

My project has focused on understanding the structural organization of the clostridial neurotoxins, botulinum and tetanus, that are the causative agents of the neuroparalytic diseases botulism and tetanus. Once the toxins enter the bloodstream they inhibit the release of neurotransmitters required for the contraction or relaxation of muscles, resulting in debilitating paralysis. Botulinum neurotoxin is also orally toxic, whereas tetanus neurotoxin is not. Botulinum interacts with additional Clostridium botulinum proteins to form complexes that protect the neurotoxin from degradation as it passes through the host’s gastrointestinal tract. Using electron microscopy techniques, I have produced novel structural insights into the molecular organization of the three botulinum neurotoxin progenitor complexes responsible for human botulism. This dissertation also reports analysis of the tetanus holotoxin structure.