Observation of Oligomeric States Indicates a High Structural Flexibility Required for the Onset of Polyglutamine Fibrillization

Polyglutamine (polyQ) diseases are caused by misfolding and aggregation ofexpanded polyQ tracts in the affected protein. PolyQfibrils have been studied in detail;however, less is known about oligomeric precursor states. By a combination of time-resolvedtemperature-jump (T-jump) infrared (IR) spectroscopy and an appropriately tailored polyQmodel peptide, we succeeded in disentangling conformational dynamics in the heterogeneousensemble of states evolving during aggregation. Individual structural elements could bedifferentiated by IR-specific signatures, i.e., hairpin monomers,beta-structured oligomers, anddisordered structure. Submillisecond dynamics were observed for early oligomeric states incontrast to the slow dynamics offibril growth. We propose that a high structuralflexibility ofoligomers is required to initiatefibril formation, but not after afibrillar structure hasconsolidated and thefibril just grows. Our study reveals that structuralflexibility changes atdifferent stages in the aggregation process, from fibril initiation to fibril growth