Huntington's disease (HD), a genetic neurodegenerative disease, is caused by an expanded polyglutamine (polyQ) domain in the first exon of the huntingtin protein (htt). PolyQ expansion destabilizes protein structure, resulting in aggregation into a variety of oligomers, protofibrils, and fibrils. Beyond the polyQ domain, adjacent protein sequences influence the aggregation process. Specifically, the first 17 N-terminal amino acids (Nt17) directly preceding the polyQ domain promote the formation of α-helix-rich oligomers that represent intermediate species associated with fibrillization. Due to its propensity to form an amphipathic α-helix, Nt17 also facilitates lipid binding. Three lysine residues (K6, K9, and K15) within Nt17 can be SUMOylated, which modifies htt's accumulation and toxicity within cells in a variety of HD models. The impact of SUMOylation on htt aggregation and direct interaction with lipid membranes was investigated. SUMOylation of htt-exon1 inhibited fibril formation while promoting larger, amorphous aggregate species. These amorphous aggregates were SDS soluble but nonetheless exhibited levels of β-sheet structure similar to that of htt-exon1 fibrils. In addition, SUMOylation prevented htt binding, aggregation, and accumulation on model lipid bilayers comprised of total brain lipid extract. Collectively, these observations demonstrate that SUMOylation promotes a distinct htt aggregation pathway that may affect htt toxicity.

中文翻译：

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SUMOylation可防止亨廷顿蛋白原纤维化和脂膜上的定位。

亨廷顿舞蹈病（HD）是一种遗传性神经退行性疾病，由亨廷顿蛋白（htt）第一个外显子中的聚谷氨酰胺（polyQ）域扩展引起。PolyQ扩展会破坏蛋白质结构的稳定性，导致聚集为各种寡聚物，原纤维和原纤维。除了polyQ结构域外，相邻的蛋白质序列也会影响聚集过程。具体而言，在polyQ域之前的前17个N末端氨基酸（Nt17）促进了富含α-螺旋的低聚物的形成，这些低聚物代表与原纤维化相关的中间物种。由于其倾向于形成两亲性α-螺旋，因此Nt17也促进脂质结合。Nt17中的三个赖氨酸残基（K6，K9和K15）可以被SUMOylated，从而在多种HD模型中修饰HTT在细胞内的积累和毒性。研究了SUMOylation对htt聚集和与脂膜的直接相互作用的影响。htt-exon1的SUMOylation抑制原纤维形成，同时促进更大的无定形聚集体物种。这些无定形聚集体可溶于SDS，但仍表现出与htt-exon1原纤维相似的β-折叠结构水平。另外，SUMOylation阻止了htt在由总脑脂质提取物组成的模型脂质双层上的结合，聚集和积聚。总体而言，这些观察结果表明SUMOylation促进了可能影响htt毒性的独特htt聚集途径。这些无定形聚集体可溶于SDS，但仍表现出与htt-exon1原纤维相似的β-折叠结构水平。另外，SUMOylation阻止了htt在由总脑脂质提取物组成的模型脂质双层上的结合，聚集和积聚。总体而言，这些观察结果表明SUMOylation促进了可能影响htt毒性的独特htt聚集途径。这些无定形聚集体可溶于SDS，但仍表现出与htt-exon1原纤维相似的β-折叠结构水平。另外，SUMOylation阻止了htt在由总脑脂质提取物组成的模型脂质双层上的结合，聚集和积聚。总体而言，这些观察结果表明SUMOylation促进了可能影响htt毒性的独特htt聚集途径。