Abstract

The abnormal expansion of polyglutamine (polyQ) tracts above a threshold length within proteins is associated with an increased propensity of the protein to aggregate into amyloid fibrils. Such expansions in nine human proteins lead to nine distinct neurodegenerative amyloidoses. While repeat length and aggregation are well correlated, the non-polyQ regions of these proteins can also play a very significant role, both preventative and facilitative, in the aggregation process. We engineered chimeric proteins via the insertion of polyQ repeats of various lengths at different locations of a model protein scaffold, the β-lactamase BlaP and we investigate the impact of polyQ position on the structure, stability, and aggregation propensity of the enzyme. The results of these experiments highlight the environment-sensitivity of polyQ protein aggregation, particularly with regards to the stability/dynamics of the host protein and to the properties of sequences flanking the polyQ tract, and contribute to a better understanding of how the overall protein context modulates the amyloid fibril-forming propensity of polyQ-containing proteins.