So far >180 mutations have been identified within the 153-residue human SOD1 to cause familial amyotrophic lateral sclerosis (FALS), while wild-type (WT) SOD1 was intriguingly implicated in sporadic ALS (SALS). SOD1 mutations lead to ALS by a dominant gain of cytotoxicity but its mechanism still remains elusive. Previously functional studies have revealed that SOD1 mutants became unexpectedly associated with organelle membranes. Indeed we decoded that the ALS-causing truncation mutant L126Z-SOD1 with an elevated toxicity completely loses the ability to fold into the native β-barrel structure but acquire a novel capacity to interact with membranes by forming helices over hydrophobic/amphiphilic segments. Very recently, the abnormal insertion of SOD1 mutants into ER membrane has been functionally characterized to trigger ER stress, an initial event of a cascade of cell-specific damages in ALS pathogenesis. Here we attempted to understand the mechanism for gain of cytotoxicity of the WT SOD1. We obtained atomic-resolution evidence that the nascent WT SOD1 without metalation and disulfide bridge is also highly disordered as L126Z. Most importantly, it owns the same capacity in interacting with membranes by forming very similar helices over the first 125 residues identical to L126Z-SOD1, plus an additional hydrophobic helix over Leu144-Ala152. Our study thus implies that the WT and mutant SOD1 indeed converge on a common mechanism for gain of cytotoxicity by abnormally interacting with membranes. Moreover, any genetic/environmental factors which can delay or impair its maturation might act to transform SOD1 into cytotoxic forms with the acquired capacity to abnormally interact with membranes.

译文

到目前为止,已经在153残基人SOD1中发现了180个突变,导致家族性肌萎缩性侧索硬化症 (fars),而野生型 (WT) SOD1有趣地与散发性ALS (ALS) 有关。SOD1突变通过细胞毒性的优势获得导致ALS,但其机制仍然难以捉摸。先前的功能研究表明,SOD1突变体与细胞器膜意外相关。实际上,我们解码出毒性升高的ALS引起截断突变体L126Z-SOD1完全失去了折叠成天然 β-桶结构的能力,但通过在疏水/两亲链段上形成螺旋而获得了与膜相互作用的新能力。最近,SOD1突变体异常插入ER膜的功能已被表征为触发ER应激,这是ALS发病机理中细胞特异性损伤级联的初始事件。在这里,我们试图了解获得WT sod1细胞毒性的机制。我们获得了原子分辨率的证据,表明没有金属化和二硫键的新生WT SOD1也与L126Z高度无序。最重要的是,通过在与膜相同的前125个残基上形成非常相似的螺旋,加上在Leu144-Ala152上形成额外的疏水螺旋,它具有与L126Z-SOD1相互作用的相同能力。因此,我们的研究表明,WT和突变体SOD1确实通过与膜异常相互作用而收敛于获得细胞毒性的共同机制。此外,任何可能延迟或损害其成熟的遗传/环境因素都可能将SOD1转化为具有与膜异常相互作用的获得性能力的细胞毒性形式。

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