Deriu Marco A, Grasso Gianvito, Tuszynski Jack A, Massai Diana, Gallo Diego, Morbiducci Umberto, Danani Andrea
Istituto Dalle Molle Di Studi Sull'intelligenza Artificiale (IDSIA), Scuola Universitaria Professionale Della Svizzera Italiana (SUPSI), Università Della Svizzera Italiana (USI), Centro Galleria 2, Manno, CH-6928, Switzerland.
Department of Physics, University of Alberta, Edmonton, Alberta, Canada.
Proteins. 2016 May;84(5):666-73. doi: 10.1002/prot.25017. Epub 2016 Mar 9.
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.
ataxin-1是导致1型脊髓小脑共济失调的蛋白质，这是一种由多聚谷氨酰胺扩增引起的无法治愈的神经退行性疾病。AXH结构域在ataxin-1的生理功能中起关键作用。在1型脊髓小脑共济失调中，AXH结构域参与错误折叠和聚集途径。本文应用分子建模来研究有助于AXH二聚体稳定性的蛋白质-蛋白质相互作用。特别关注：（i）AXH单体-单体界面的表征；（ii）AXH单体-单体相互作用动力学的分子描述。在技术上，采用了一种基于功能模式分析的方法，这里应用于副本交换分子动力学轨迹。本研究的结果与先前的实验结果一致，并阐明了I580残基在介导AXH单体-单体相互作用动力学中的关键作用。
