Spinocerebellar ataxia type 1 is late-onset neurodegenerative diseases caused by the expansion of a CAG triplet repeat in the SCA1 gene. This results in the lengthening of a polyglutamine tract in the gene product ataxin-1 producing a toxic gain of function that results in neuronal death.
The crystal structure of the AXH domain of ataxin-1 has been determined as it exhibits significant sequence similarity to the transcription factor HBP1 [ (PUBMED:12965213) ] and has been implicated in RNA binding and self-association. The AXH domain is dimeric and contains an OB-fold, a structural motif found in many oligonucleotide-binding proteins. By comparison to other proteins that contain an OB-fold, the putative RNA-binding region has been identified. In addition, there are a number of well-conserved residues that form a second ligand-binding surface, suggesting that AXH domains interact with a common yet unidentified partner [ (PUBMED:14583607) ].
Identification of a self-association region within the SCA1 gene product, ataxin-1.
Hum Mol Genet. 1997; 6: 513-8
Display abstract
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of a polyglutamine tract within the SCA1 gene product, ataxin-1. Expansion of this tract is believed to result in a gain of function by the mutant protein, perhaps through altered self-associations or interactions with other cellular proteins. We have used the yeast two hybrid system to determine if ataxin-1 is capable of multimerization. This analysis revealed that ataxin-1 does have the ability to self-associate, however, this association does not appear to be influenced by expansion of the polyglutamine tract. Consistent with this finding, deletion analysis excluded the involvement of the polyglutamine tract in ataxin-1 self-association, and instead localized the multimerization region to amino acids 495-605 of the wild type protein. These results, while identifying an ataxin-1 self-interaction region, fail to support a proposed model of polar-zipper mediated multimerization involving the ataxin-1 polyglutamine tract.
