Yosuke Kondo and Satoru Miyazaki
Botulinum neurotoxins (BoNTs) are one of the potent toxins in nature but the toxicity is immediately eliminated by the harsh environment in the digestive tract because BoNTs are just a protein. However, BoNTs can get to synaptic junctions thanks to support of other proteins by aggregating with each other, combining with BoNTs and forming a large progenitor toxin complex (L-PTC). In order to explain how the complex formation enables the BoNTs to intrude into our body, we found that the three-dimensional structure of the L-PTC consists of an ovoid body with three legs and speculated important roles in the body and the legs. In the legs part, it is helpful for promoting absorption especially from the small intestine. Because experimental results showed that the legs are flexible and have specific binding sites of saccharides, the flexibilities may help the L-PTC to easily access the binding sites to the saccharides on the intestinal surface. However, such flexibilities have been only investigated by experimental methods. This means that we still have not objectively discussed what motions are generated from the shape of the L-PTC and how the structure is changed gradually. Therefore, we developed a new method integrating an analysis based on anisotropic network model and principal component analyses in order to measure the dynamics of the large-sized protein consisting of several subunits. The results showed that the L-PTC had characteristic motions which have large movements of the three legs. In addition, the flexible motions were appeared regardless of the theoretical models. Our application to measure the dynamics of the L- PTC suggested the importance of the flexibility which enables the L-PTC to break the epithelial barrier. We hope that the activity of the L-PTC is applied for developing a new oral drug delivery system.
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