Structural and dynamic studies reveal that the Ala-rich region of ataxin-7 initiates α-helix formation of the polyQ tract but suppresses its aggregation

• Published in: Scientific reports Vol. 9; no. 1; p. 7481
• Main Authors: Hong, Jun-Ye, Wang, Dong-Dong, Xue, Wei, Yue, Hong-Wei, Yang, Hui, Jiang, Lei-Lei, Wang, Wen-Ning, Hu, Hong-Yu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.05.2019; Nature Publishing Group
• Subjects: 140/131; 631/45/470/2284; 631/57/2272; 82; Alanine; Amyloid; Amyloid - chemistry; Amyloid - metabolism; Ataxia; Ataxin; Ataxin-7 - chemistry; Ataxin-7 - metabolism; Disease; HEK293 Cells; Humanities and Social Sciences; Humans; Laboratories; Molecular Dynamics Simulation; multidisciplinary; N-Terminus; Pathogenesis; Peptides - chemistry; Polyglutamine; Population; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Multimerization; Proteins; Science; Science (multidisciplinary); Spinocerebellar ataxia; Trinucleotide repeat diseases
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-43926-9

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.