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Toxicity of the prion molecule is a result of transmission of conformational change by direct contact with malignant misfolded molecule. The aim of this study is analyze the role of D278N mutation in promoting preferential oligomerization modes. Proteins exist as ensembles in equilibrium between different structural and dynamic states, including functionally relevant conformers as the most populated states as well as malfunctioning conformers as less populated states. Furthermore, the existence of different conformations allows protein oligomerization with condition-specific affinities. The maintenance of a particular role requires specific conversion between multiple stable states. Protein-protein binding may facilitate or may be a necessary condition of structural adaptation. In the case of prion disease, protein-protein interactions, resulting in prion agglomeration, have toxic effect. How exactly increased concentrations of prion oligomers trigger mechanisms leading to neuronal death is not known. Nevertheless, first oligomerization and second aggregate recognition are likely sequence of events that have to happen before any pathological condition may arise. Here, we carry out structural and dynamic analyses of the effect of disease-causing mutations on the dimerization and tetramerization of prion molecule as the first step in aggregate formation. D178N mutation has almost no effect on the monomeric structure but helps to stabilize the dimer, which consequently facilitates tetramer formation and stability.

Role of D278N mutation for stability of prion dimer and tetramer structure