Botulinum neurotoxins

Sammanfattning: Botulinum neurotoxins (BoNTs) are the most potent toxins known to man, with less than 1 μg of pure toxin being enough to kill an adult man. Despite the high toxicity, BoNTs are widely used in cosmetics and in medicine for the treatment of an increasing number of medical conditions.BoNTs have a conserved structure that consists of three domains (a receptor binding, translocation, and catalytic domain). The receptor binding domain is responsible for binding to neuronal receptors, the translocation domain is a delivery vehicle that transports the catalytic domain into the cytosol, where the latter cleaves its target - proteins of the SNARE family, inhibiting neurotransmitter release and consequently causing muscle paralysis.BoNTs are produced by the bacteria Clostridium botulinum together with several other accessory proteins, which are responsible for shielding BoNTs in the harsh environment of the target gastrointestinal tract and assisting them in crossing the epithelial barrier between the gastrointestinal tract and general circulation.Several BoNT serotypes (A-G) have been identified over the years. Additionally, several BoNT-like toxins have been identified in non-Clostridial types of bacteria. Namely, these proteins are BoNT/Wo, BoNT/En and PMP1.In this thesis, we present six papers, where we studied both the canonical BoNTs and the new BoNT-like toxins as well as their accessory proteins using structural biology techniques, such as X-ray crystallography and cryo-EM. Elucidating the structures of these proteins is crucial for understanding their function and mechanism of action.