NMR study of the formation and dissolution mechanisms of Sup35 amyloid fibrils.

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Protein aggregates (amyloid) are common pathological feature of most neurodegenerative diseases. In this study, I investigated the molecular mechanism controlling of determination of amyloid structural polymorphism which affects the clinical state of such diseases, using a yeast prion protein, Sup35. From measurements of several NMR methods focusing on the Sup35 structural fluctuation and local conformation, I found two amyloid initiation sites on Sup35 sequence. Thus, it was conceivable that amyloid structural polymorphism arises from the competition of these two sites. Next, I found the relatively compact local conformation in a part of WT Sup35NM. This result exhibited that the one initiation site is included in this compact area, so another site is advantageous in WT amyloid formation. In conclusion, it was suggested that amyloid structural polymorphism is induced by the destruction of local conformation by amino acid substitution.