Characterization of the AXH domain of Ataxin‐1 using enhanced sampling and functional mode analysis. Issue 5 (9th March 2016)

• Record Type: Journal Article
• Authors: Deriu, Marco A.; Grasso, Gianvito; Tuszynski, Jack A.; Massai, Diana; Gallo, Diego; Morbiducci, Umberto; Danani, Andrea
• Is Part Of: Proteins. Volume 84:Issue 5(2016)
• Page Start: 666
• Page End: 673
• Publication Date: 2016-03-09
• Subjects: neurodegenerative -- replica exchange molecular dynamics -- Ataxin -- functional mode analysis -- protein−protein interactions -- dimer -- AXH -- conformational stability; Proteins -- Periodicals; Proteins -- Periodicals; 572.6
• DOI: 10.1002/prot.25017
• Languages: English
• ISSNs: 0887-3585

Abstract

ABSTRACT: Ataxin‐1 is the protein responsible for the Spinocerebellar ataxia type 1, an incurable neurodegenerative disease caused by polyglutamine expansion. The AXH domain plays a pivotal role in physiological functions of Ataxin‐1. In Spinocerebellar ataxia 1, the AXH domain is involved in the misfolding and aggregation pathway. Here molecular modeling is applied to investigate the protein‐protein interactions contributing to the AXH dimer stability. Particular attention is focused on: (i) the characterization of AXH monomer‐monomer interface; (ii) the molecular description of the AXH monomer‐monomer interaction dynamics. Technically, an approach based on functional mode analysis, here applied to replica exchange molecular dynamics trajectories, was employed. The findings of this study are consistent with previous experimental results and elucidate the pivotal role of the I580 residue in mediating the AXH monomer‐monomer interaction dynamics. Proteins 2016; 84:666–673. © 2016 Wiley Periodicals, Inc.