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Abstract
Ataxin-7 (Atx7) is a disease-related protein associated with the pathogenesis of spinocerebellar ataxia 7, while its polyglutamine (polyQ) tract in N-terminus is the causative source of aggregation and proteinopathy. We investigated the structure, dynamics and aggregation properties of the N-terminal 62-residue fragment of Atx7 (Atx7-N) by biochemical and biophysical approaches. The results showed that the normal Atx7-N with a tract of 10 glutamines (10Q) overall adopts a flexible and disordered structure, but it may contain a short or small population of helical structure in solution. PolyQ expansion increases the α-helical propensity of the polyQ tract and consequently enhances its transformation into β-sheet structures during amyloid aggregation. An alanine-rich region (ARR) just ahead of the polyQ tract forms a local and relatively stable α-helix. The ARR α-helix can initiate and stabilize helical formation of the following polyQ tract, but it may suppress aggregation of the polyQ-expanded Atx7-N both in vitro and in cell. Thus, the preceding ARR segment in Atx7-N may influence the dynamic structure and aggregation property of the polyQ tract and even determine the threshold of the pathogenic polyQ lengths. This study may gain structural and dynamic insights into amyloid aggregation of Atx7 and help us further understand the Atx7 proteinopathy based on polyQ expansion.
Highlights
Ataxin-7 (Atx7) is a disease-related protein associated with the pathogenesis of spinocerebellar ataxia 7, while its polyglutamine tract in N-terminus is the causative source of aggregation and proteinopathy
ARR, alanine-rich region consisting of ARR1 and ARR2 motifs; polyQ, polyglutamine tract; PRR, proline-rich region. (B,C) Supernatant/pellet fractionation assay for aggregation of Atx710Q-N (B) and Atx733Q-N (C) during incubation
The disease-related polyQ proteins are relatively large in size and often composed of multiple domains
Summary
Ataxin-7 (Atx7) is a disease-related protein associated with the pathogenesis of spinocerebellar ataxia 7, while its polyglutamine (polyQ) tract in N-terminus is the causative source of aggregation and proteinopathy. The expanded CAG repeats are translated into an uninterrupted series of glutamine residues, which is known as a polyglutamine (polyQ) tract. Such expansion of the polyQ tract can cause protein aggregation and is believed to be the causative source of cytotoxicity and neurodegeneration[1,2,3]. Has been shown to form marginal or partial α-helix structure that is recognized by HSP90 and enhances Htt aggregation[18], whereas the C-terminal flanking proline-rich region (PRR) tends to attenuate aggregation[13,15,17]
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