Smaoui Mohamed R, Mazza-Anthony Cody, Waldispühl Jérôme
Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada; Institut de Recherches Cliniques de Montreal (IRCM), Montreal, QC, Canada.
School of Computer Science, McGill University, Montreal, QC, Canada.
Comput Math Methods Med. 2016;2016:6247867. doi: 10.1155/2016/6247867. Epub 2016 Dec 14.
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.
亨廷顿舞蹈症是一种致命的常染色体显性遗传病，其特征是亨廷顿蛋白（Htt）外显子1基因中的谷氨酰胺编码CAG重复序列发生扩增。与该疾病相关的Htt蛋白错误折叠成有毒的寡聚体和聚集纤维结构。关于错误折叠和聚集现象的竞争模型表明，Htt的N端区域和CAG三核苷酸重复序列（polyQ结构域）在影响聚集倾向和错误折叠方面发挥了作用。具体而言，一种模型认为结构稳定性与有毒寡聚体的出现之间存在关联，而另一种模型则提出与延伸的polyQ结构域的分子相互作用会增加聚集倾向。在本文中，我们通过解决两种模型中概述的聚集原因，以计算方式探索降低Htt聚集的潜力。我们研究了Htt N端区域的突变情况，并探索了影响其结构稳定性以及与polyQ结构域疏水相互作用的氨基酸残基突变。在我们探索的数百万种三点突变组合中，（L4K E12K K15E）是最有前景的突变组合，它解决了两种模型中的聚集原因。突变体结构表现出极高的α螺旋稳定性、低淀粉样变性潜力、疏水残基替换以及去除了有助于寡聚化的溶剂不可及的分子间侧链。
