Evolutionary model of repeat insertions in Ataxin-3 traces the origin of the polyglutamine stretch to an ancestral ubiquitin binding module.

The human ataxin-3 protein contains an N-terminal Josephin domain, composed of a papain-like cysteine protease with a helical hairpin insertion, and a C-terminal region with two or three ubiquitin interacting motifs and a polyglutamine tract. Expansion of the polyglutamine tract leading to protein aggregation and neuronal degradation has been linked to Machado-Joseph disease/spinocerebellar ataxia type 3, the most common form of dominantly inherited ataxia. In this study, we performed sequence self-homology dot plot analysis and compared orthologous proteins to analyze the architecture of ataxin-3 during the evolution of Filozoa. This analysis uncovered up to three additional repetitions of the ubiquitin binding motif in ataxin-3, including the helical hairpin insertion in the Josephin domain, and revealed a highly conserved multimodular architecture that is broadly preserved throughout the Filozoa. Overall, a set of 78 putative ubiquitin binding repeats from 18 exemplar proteins were identified. Apparent neofunctionalization events could also be recognized, including modification of repeat 5 which gave rise to the disease-linked polyglutamine tract, just before the Sarcopterygian divergence. This model provides a unifying principle for the ataxin-3 protein architecture and can potentially provide new insights into the role of molecular interactions in ataxin-3 function and Machado-Joseph disease/spinocerebellar ataxia type 3 disease mechanisms.