Molecular chaperones maintain protein homeostasis (proteostasis) by ensuring the proper folding of polypeptides. Loss of proteostasis has been linked to the onset of numerous neurodegenerative disorders including Alzheimer's, Parkinson's, and Huntington's disease. Hsp110 is related to the canonical Hsp70 class of protein folding molecular chaperones and interacts with Hsp70 as a nucleotide exchange factor (NEF), promoting rapid cycling of ADP for ATP. In addition to its NEF activity, Hsp110 possesses an Hsp70-like substrate binding domain (SBD) whose biological roles remain undefined. Previous work in Drosophila melanogaster has shown that loss of the sole Hsp110 gene (Hsc70cb) accelerates the aggregation of polyglutamine (polyQ)-expanded human Huntingtin, while its overexpression protects against polyQ-mediated neuronal cell death. We hypothesize that in addition to its role as an Hsp70 NEF, Drosophila Hsp110 may function in the fly as a protective protein "holdase", preventing the aggregation of unfolded polypeptides via the SBD-γ subdomain. Using an in vitro protein aggregation assay we demonstrate for the first time that Drosophila Hsp110 effectively prevents aggregation of the model substrate citrate synthase. We also report the discovery of a redundant and heretofore unknown potent holdase capacity in a 138 amino-acid region of Hsp110 carboxyl-terminal to both SBD-γ and SBD-α (henceforth called the C-terminal extension). This sequence is highly conserved in metazoan Hsp110 genes, completely absent from fungal representatives, including Saccharomyces cerevisiae SSE1, and is computationally predicted to contain an intrinsically disordered region (IDR). We demonstrate that this IDR sequence within the human Hsp110s, Apg-1 and Hsp105α, inhibits the formation of amyloid Aβ-42 and α-synuclein fibrils in vitro but cannot mediate fibril disassembly. Together these findings demonstrate the existence of a second independent, passive holdase property of metazoan Hsp110 chaperones capable of suppressing both general protein aggregation and amyloidogenesis and raise the possibility of exploitation of this IDR for therapeutic benefit in combating neurodegenerative disease.

中文翻译：

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后生动物Hsp110伴侣分子中的一个新的内在无序区域的抑制聚集体和淀粉样蛋白形成。

分子伴侣蛋白通过确保多肽的正确折叠来维持蛋白质稳态（蛋白稳态）。蛋白变性丧失与许多神经退行性疾病的发作有关，包括阿尔茨海默氏症，帕金森氏症和亨廷顿氏病。Hsp110与蛋白质折叠分子伴侣的经典Hsp70类有关，并与Hsp70作为核苷酸交换因子（NEF）相互作用，从而促进ADP对ATP的快速循环。除了其NEF活性外，Hsp110还具有Hsp70样底物结合域（SBD），其生物学作用仍然不确定。果蝇的先前工作已有研究表明，唯一的Hsp110基因（Hsc70cb）缺失会加速多聚谷氨酰胺（polyQ）扩增的人类Huntingtin的聚集，而其过表达则可防止polyQ介导的神经元细胞死亡。我们假设除了果蝇作为Hsp70 NEF的作用之外，果蝇Hsp110可能在飞行中充当保护性蛋白质“保持酶”，从而防止未折叠的多肽通过SBD-γ亚结构域聚集。使用体外蛋白质聚集测定法，我们首次证明果蝇Hsp110有效地阻止了模型底物柠檬酸合酶的聚集。我们还报告了在Hsp110羧基末端的138个氨基酸的SBD-γ和SBD-α的138个氨基酸区域（以下称为C末端延伸）中发现了一个冗余且迄今未知的强力保持酶能力。此序列在后生动物Hsp110基因中高度保守，而真菌代表（包括酿酒酵母SSE1）完全不存在，并通过计算预测包含一个固有无序区（IDR）。我们证明了人类Hsp110s，Apg-1和Hsp105α中的IDR序列在体外可抑制淀粉样蛋白Aβ-42和α-突触核蛋白原纤维的形成，但不能介导原纤维的分解。这些发现共同证明了后生动物Hsp110分子伴侣具有第二种独立的，被动的保持酶特性，能够抑制一般的蛋白质聚集和淀粉样蛋白生成，并增加了利用该IDR对抗神经退行性疾病的治疗益处。