Characterization of the L-ferritin variant 460InsA responsible of a hereditary ferritinopathy disorder
Characterization of the L-ferritin variant 460InsA responsible of a hereditary ferritinopathy disorder
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DOI：
10.1016/j.nbd.2006.05.004
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发表时间：
2006-09-01
影响因子：
6.1
通讯作者：
Levi, Sonia
中科院分区：
文献类型：
--
作者：
Cozzi, Anna;Santambrogio, Paolo;Levi, Sonia
遗传性铁蛋白病是一种显性遗传性运动障碍，与L铁蛋白C端肽的广泛改变有关，其原因是L铁蛋白基因(FTL)的核苷酸插入。我们描述了最常见的变异的特征，由460InsA突变产生，这里称为LN1。重组的LN1以低效率组装成24聚铁蛋白壳，然而，它能够在体外形成杂多聚体，显示出结合铁的能力降低。在HeLa细胞中表达的LN1形成了含有内源性H链和L链的杂交铁蛋白，并导致了铁过量的表型。铁蛋白的失活和LN1细胞更快的降解同时提高了铁的利用率，这可能是其对H_2O_2毒性的敏感性更高和氧化蛋白水平更高的原因。这些发现表明，LN1表达的致病效应更有可能是由于细胞铁稳态的解除调节，而不是蛋白质构象问题。(C)2006 Elsevier Inc.保留所有权利。
Hereditary ferritinopathies are dominant inherited movement disorders associated with extensive alterations of the L-ferritin C-terminus peptide caused by nucleotide insertions in L-ferritin gene (FTL). We describe the characterization of the most common variant, produced by the 460InsA mutations and here named Ln1. The recombinant Ln1 assembled into 24-mer ferritin shells with low efficiency, however, it was able to form heteropolymers that showed a reduced capacity to incorporate iron in vitro. The Ln1 expressed in HeLa cells formed hybrid ferritins, with the endogenous H and L chains, and caused an iron excess phenotype. Ferritin inactivation and faster degradation in Ln1 transfectants concurred in increasing iron availability, which was probably responsible for the higher sensitivity to H2O2 toxicity and higher level of oxidized proteins. The findings suggest that the pathogenic effects of Ln1 expression are more likely due to deregulation of cellular iron homeostasis rather than to protein conformational problems. (c) 2006 Elsevier Inc. All rights reserved.