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The Josephin domain determines the morphological and mechanical properties of ataxin-3 fibrils.

ABSTRACT: Fibrillar aggregation of the protein ataxin-3 is linked to the inherited neurodegenerative disorder Spinocerebellar ataxia type 3, a member of the polyQ expansion disease family. We previously reported that aggregation and stability of the nonpathological form of ataxin-3, carrying an unexpanded polyQ tract, are modulated by its N-terminal Josephin domain. It was also shown that expanded ataxin-3 aggregates via a two-stage mechanism initially involving Josephin self-association, followed by a polyQ-dependent step. Despite this recent progress, however, the exact mechanism of ataxin-3 fibrilization remains elusive. Here, we have used electron microscopy, atomic force microscopy, and other biophysical techniques to characterize the morphological and mechanical properties of nonexpanded ataxin-3 fibrils. By comparing aggregates of ataxin-3 and of the isolated Josephin domain, we show that the two proteins self-assemble into fibrils with markedly similar features over the temperature range 37-50°C. Estimates of persistence length and Young's modulus of the fibrils reveal a great flexibility. Our data indicate that, under physiological conditions, during early aggregation Josephin retains a nativelike secondary structure but loses its enzymatic activity. The results suggest a key role of Josephin in ataxin-3 fibrillar aggregation.

SUBMITTER: Masino L

PROVIDER: S-EPMC3077691 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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The Josephin domain determines the morphological and mechanical properties of ataxin-3 fibrils.

Masino Laura L Nicastro Giuseppe G De Simone Alfonso A Calder Lesley L Molloy Justin J Pastore Annalisa A

Biophysical journal 20110401 8

Fibrillar aggregation of the protein ataxin-3 is linked to the inherited neurodegenerative disorder Spinocerebellar ataxia type 3, a member of the polyQ expansion disease family. We previously reported that aggregation and stability of the nonpathological form of ataxin-3, carrying an unexpanded polyQ tract, are modulated by its N-terminal Josephin domain. It was also shown that expanded ataxin-3 aggregates via a two-stage mechanism initially involving Josephin self-association, followed by a po ...[more]

PMID: 21504740

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Dataset Information

The Josephin domain determines the morphological and mechanical properties of ataxin-3 fibrils.

Publications

The Josephin domain determines the morphological and mechanical properties of ataxin-3 fibrils.

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