Unknown

Dataset Information

0

Flanking domain stability modulates the aggregation kinetics of a polyglutamine disease protein.


ABSTRACT: Spinocerebellar Ataxia Type 3 (SCA3) is one of nine polyglutamine (polyQ) diseases that are all characterized by progressive neuronal dysfunction and the presence of neuronal inclusions containing aggregated polyQ protein, suggesting that protein misfolding is a key part of this disease. Ataxin-3, the causative protein of SCA3, contains a globular, structured N-terminal domain (the Josephin domain) and a flexible polyQ-containing C-terminal tail, the repeat-length of which modulates pathogenicity. It has been suggested that the fibrillogenesis pathway of ataxin-3 begins with a non-polyQ-dependent step mediated by Josephin domain interactions, followed by a polyQ-dependent step. To test the involvement of the Josephin domain in ataxin-3 fibrillogenesis, we have created both pathogenic and nonpathogenic length ataxin-3 variants with a stabilized Josephin domain, and have both stabilized and destabilized the isolated Josephin domain. We show that changing the thermodynamic stability of the Josephin domain modulates ataxin-3 fibrillogenesis. These data support the hypothesis that the first stage of ataxin-3 fibrillogenesis is caused by interactions involving the non-polyQ containing Josephin domain and that the thermodynamic stability of this domain is linked to the aggregation propensity of ataxin-3.

SUBMITTER: Saunders HM 

PROVIDER: S-EPMC3218360 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

altmetric image

Publications

Flanking domain stability modulates the aggregation kinetics of a polyglutamine disease protein.

Saunders Helen M HM   Gilis Dimitri D   Rooman Marianne M   Dehouck Yves Y   Robertson Amy L AL   Bottomley Stephen P SP  

Protein science : a publication of the Protein Society 20110818 10


Spinocerebellar Ataxia Type 3 (SCA3) is one of nine polyglutamine (polyQ) diseases that are all characterized by progressive neuronal dysfunction and the presence of neuronal inclusions containing aggregated polyQ protein, suggesting that protein misfolding is a key part of this disease. Ataxin-3, the causative protein of SCA3, contains a globular, structured N-terminal domain (the Josephin domain) and a flexible polyQ-containing C-terminal tail, the repeat-length of which modulates pathogenicit  ...[more]

Similar Datasets

| S-EPMC2890844 | biostudies-literature
| S-EPMC3170924 | biostudies-other
| S-EPMC4156672 | biostudies-literature
| S-EPMC3448832 | biostudies-literature
| S-EPMC3468392 | biostudies-literature
| S-EPMC3767516 | biostudies-literature
| S-EPMC7907447 | biostudies-literature
| S-EPMC4049302 | biostudies-literature
| S-EPMC2965175 | biostudies-literature
| S-EPMC3701761 | biostudies-literature