Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia
Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia
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DOI：
10.7554/elife.17983
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发表时间：
2016-08-04
期刊：
影响因子：
7.7
通讯作者：
Schwartz, Thomas U.
中科院分区：
文献类型：
--
作者：
Demircioglu, F. Esra;Sosa, Brian A.;Schwartz, Thomas U.
早发性原发性肌张力障碍是一种神经肌肉疾病，其最常见的原因是TorsinA（一种位于内质网的AAA+ atp酶）302/303位的谷氨酸缺失（Delta E）。虽然TorsinA的功能仍然难以捉摸，但已知Delta E突变会减少两种TorsinA atp酶激活因子的结合：层相关蛋白1 （LAP1）及其类似的腔内结构域LAP1 （LULL1）。利用纳米体作为结晶伴侣，我们获得了人类TorsinA与LULL1复合物的1.4埃晶体结构。该纳米体同样稳定了减弱的TorsinA Delta E-LULL1相互作用，这也使我们能够在1.4埃下解出其结构。这些结构的比较显示，在原子细节上，激活剂相互作用的细微差异，将健康状态与患病状态分开。这一信息可能为药物开发提供一个结构平台，因为一种拯救TorsinA Delta E的小分子可以作为原发性肌张力障碍的治疗方法。
The most common cause of early onset primary dystonia, a neuromuscular disease, is a glutamate deletion (Delta E) at position 302/303 of TorsinA, a AAA+ ATPase that resides in the endoplasmic reticulum. While the function of TorsinA remains elusive, the Delta E mutation is known to diminish binding of two TorsinA ATPase activators: lamina-associated protein 1 (LAP1) and its paralog, luminal domain like LAP1 (LULL1). Using a nanobody as a crystallization chaperone, we obtained a 1.4 angstrom crystal structure of human TorsinA in complex with LULL1. This nanobody likewise stabilized the weakened TorsinA Delta E-LULL1 interaction, which enabled us to solve its structure at 1.4 angstrom also. A comparison of these structures shows, in atomic detail, the subtle differences in activator interactions that separate the healthy from the diseased state. This information may provide a structural platform for drug development, as a small molecule that rescues TorsinA Delta E could serve as a cure for primary dystonia.