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

Mohamed R Smaoui,Jérôme Waldispühl,Cody Mazza-Anthony

doi:10.1155/2016/6247867

Mohamed R Smaoui, Jérôme Waldispühl + Show 1 more

Open Access

https://doi.org/10.1155/2016/6247867

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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.

Highlights

Huntington Disease (HD) is a fatal autosomal dominant genetic disorder that is characterized by CAG trinucleotide repeats in the huntingtin (Htt) exon 1 gene [1, 2]
Parkinson’s, Alzheimer’s, and diabetes, to name a few, belong to the same amyloidosis group and have been shown to be greatly aggravated by amyloids [3,4,5]. These diseases caused or implicated by protein misfolding are usually categorized by the accumulation of insoluble amyloid proteins that form into long fibrils in the body [6]
In HD, both the alpha-helical Htt-N-terminal region and the CAG trinucleotide repeats are believed to participate in the misfolding process of the huntingtin protein into beta-sheet rich amyloids that aggregate into potentially toxic oligomeric species and fibril structures [7,8,9]

Summary

Introduction

Huntington Disease (HD) is a fatal autosomal dominant genetic disorder that is characterized by CAG trinucleotide repeats in the huntingtin (Htt) exon 1 gene [1, 2]. Parkinson’s, Alzheimer’s, and diabetes, to name a few, belong to the same amyloidosis group and have been shown to be greatly aggravated by amyloids [3,4,5] These diseases caused or implicated by protein misfolding are usually categorized by the accumulation of insoluble amyloid proteins that form into long fibrils in the body [6]. In HD, both the alpha-helical Htt-N-terminal region and the CAG trinucleotide repeats (polyQ domain) are believed to participate in the misfolding process of the huntingtin protein into beta-sheet rich amyloids that aggregate into potentially toxic oligomeric species and fibril structures [7,8,9]. The N-terminal domain has been shown to adopt an alpha-helical structure that affects aggregate formation [8] and mutations have been observed to influence fibril formation [10,11,12,13,14,15]

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