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Biophys J. 2018 Jan 23;114(2):323-330. doi: 10.1016/j.bpj.2017.11.025.

Destabilizing the AXH Tetramer by Mutations: Mechanisms and Potential Antiaggregation Strategies.

Author information

1
Istituto Dalle Molle di Studi Sull'Intelligenza Artificiale (IDSIA), Scuola Universitaria Professionale della Svizzera Italiana (SUPSI), Università della Svizzera Italiana (USI), Manno, Switzerland.
2
Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Torino, Italy.
3
Department of Physics, University of Alberta, Edmonton, Alberta, Canada.
4
Istituto Dalle Molle di Studi Sull'Intelligenza Artificiale (IDSIA), Scuola Universitaria Professionale della Svizzera Italiana (SUPSI), Università della Svizzera Italiana (USI), Manno, Switzerland. Electronic address: marco.deriu@supsi.ch.

Abstract

The AXH domain of protein Ataxin 1 is thought to play a key role in the misfolding and aggregation pathway responsible for Spinocerebellar ataxia 1. For this reason, a molecular level understanding of AXH oligomerization pathway is crucial to elucidate the aggregation mechanism, which is thought to trigger the disease. This study employs classical and enhanced molecular dynamics to identify the structural and energetic basis of AXH tetramer stability. Results of this work elucidate molecular mechanisms behind the destabilizing effect of protein mutations, which consequently affect the AXH tetramer assembly. Moreover, results of the study draw attention for the first time, to our knowledge, to the R638 protein residue, which is shown to play a key role in AXH tetramer stability. Therefore, R638 might be also implicated in the AXH oligomerization pathway and stands out as a target for future experimental studies focused on self-association mechanisms and fibril formation of full-length ATX1.

PMID:
29401430
PMCID:
PMC5984971
DOI:
10.1016/j.bpj.2017.11.025
[Indexed for MEDLINE]
Free PMC Article

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