Investigating Mutations to Reduce Huntingtin Aggregation by Increasing Htt-N-Terminal Stability and Weakening Interactions with PolyQ Domain

Author:

Smaoui Mohamed R.12ORCID,Mazza-Anthony Cody3,Waldispühl Jérôme3

Affiliation:

1. Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada

2. Institut de Recherches Cliniques de Montreal (IRCM), Montreal, QC, Canada

3. School of Computer Science, McGill University, Montreal, QC, Canada

Abstract

Huntington’s disease is a fatal autosomal genetic disorder characterized by an expanded glutamine-coding CAG repeat sequence in the huntingtin (Htt) exon 1 gene. The Htt protein associated with the disease misfolds into toxic oligomers and aggregate fibril structures. Competing models for the misfolding and aggregation phenomena have suggested the role of the Htt-N-terminal region and the CAG trinucleotide repeats (polyQ domain) in affecting aggregation propensities and misfolding. In particular, one model suggests a correlation between structural stability and the emergence of toxic oligomers, whereas a second model proposes that molecular interactions with the extended polyQ domain increase aggregation propensity. In this paper, we computationally explore the potential to reduce Htt aggregation by addressing the aggregation causes outlined in both models. We investigate the mutation landscape of the Htt-N-terminal region and explore amino acid residue mutations that affect its structural stability and hydrophobic interactions with the polyQ domain. Out of the millions of 3-point mutation combinations that we explored, the (L4K E12K K15E) was the most promising mutation combination that addressed aggregation causes in both models. The mutant structure exhibited extreme alpha-helical stability, low amyloidogenicity potential, a hydrophobic residue replacement, and removal of a solvent-inaccessible intermolecular side chain that assists oligomerization.

Publisher

Hindawi Limited

Subject

Applied Mathematics,General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Modeling and Simulation,General Medicine

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