Model systems are important tools for the investigation of pathogenic processes. Especially
for diseases with a late onset of symptoms and slow progression, like most spinocerebellar
ataxias (SCA), it is time-consuming or even impossible to analyze all aspects of the
pathogenesis in humans.
The protein ataxin-3 is responsible for spinocerebellar ataxia type 3, a neu-rodegenerative disease triggered when the length of a stretch of consecutive
glutamines exceeds a critical threshold. Different physiologic roles have
been suggested for this protein. More specifically, recent papers have
shown that the highly conserved N-terminal Josephin domain of ataxin-3
binds ubiquitin and has ubiquitin hydrolase activity, thanks to a catalytic
device specific to cysteine proteases.
Spinocerebellar ataxia types 2 (SCA2) and 3 (SCA3) are
autosomal-dominantly inherited, neurodegenerative dis-eases caused by CAG repeat expansions in the coding
regions of the genes encoding ataxin-2 and ataxin-3,
respectively. To provide a rationale for further functional
experiments, we explored the proteinarchitectures of ataxin-2 and ataxin-3. Using structure-based multiple sequence
alignments of homologous proteins, we investigated
domains, sequence motifs, and interaction partners.