Biophysical Characterisation of the Josephin Domain of Ataxin-3

The misfolding and subsequent aggregation of proteins underpins a large number of conditions called conformational diseases. Many of these diseases are caused by genetic mutations in protein coding regions. One such family is the polyglutamine diseases, characterised by the expansion of a naturally occurring glutamine repeat beyond a specific threshold length. While numerous studies have established a link between glutamine tract length and disease state, less is understood about how this expansion affect the protein’s ability to fold, and the mechanisms by which both misfolding and aggregation occur. One important observation across the polyQ diseases, is that the age of disease onset often varies widely between patients with an equal polyQ tract length. These data indicate that molecular factors other than polyQ tract length influence the misfolding and aggregation of disease-associated polyQ proteins.
   This study aims to explore factors outside of the polyQ tract which influence the misfolding and aggregation of the polyglutamine protein ataxin-3. Firstly, the impact of flanking domain mobility was assessed and shown to play a significant role in the initiation of ataxin-3 aggregation. Secondly, we have demonstrated that interactions with physiologically relevant binding partners can drastically affect the ataxin-3 aggregation mechanism. Finally, we establish that despite significant sequence and structural homology, the three Josephin proteins display markedly different aggregation profiles, suggesting a delicate interplay between protein sequence, stability, molecular mobility and aggregation propensity.

Author requested conversion to open access 27 Oct 2022