Mutations linked to Leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways
Mutations linked to Leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways
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DOI：
10.1128/mcb.24.8.3295-3306.2004
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发表时间：
2004-04-01
影响因子：
5.3
通讯作者：
Proud, CG
中科院分区：
文献类型：
--
作者：
Li, W;Wang, XM;Proud, CG
白色消失性脑白质病（Leukoencephalopathy with vanishing white matter，VWM）是一种严重的遗传性人类神经退行性疾病，由真核细胞起始因子2B（eIF 2B）亚基基因突变引起，eIF 2B是一种异五聚体鸟嘌呤核苷酸交换因子，调节全局和mRNA特异性翻译。患者VWM的临床严重程度和时间进程存在明显的变异性。在这里，我们研究了VWM突变对人eIF 2B功能的影响。所有测试的突变都会导致部分活性丧失。eIF 2B β或eIF 2B β基因中的移码突变导致截短的多肽不能与其他亚基形成复合物，并且是有效的无效突变。某些点突变还损害eIF 2B β或β-CD形成eIF 2B全复合物的能力，并降低eIF 2B的固有核苷酸交换活性。e1 F2 B β的催化结构域中的一个点突变削弱了其结合底物的能力，而eIF 2B β中的两个突变实际上增强了eIF 2的结合。我们提供的证据表明，VWM突变体eIF 2B的表达可能会增强特定mRNA的翻译。VWM临床表型的变异性可能反映了VWM突变影响eIF 2B功能的多种方式。
Leukoencephalopathy with vanishing white matter (VWM) is a severe inherited human neurodegenerative disorder that is caused by mutations in the genes for the subunits of eukaryotic initiation factor 2B (eIF2B), a heteropentameric guanine nucleotide exchange factor that regulates both global and mRNA-specific translation. Marked variability is evident in the clinical severity and time course of VWM in patients. Here we have studied the effects of VWM mutations on the function of human eIF2B. All the mutations tested cause partial loss of activity. Frameshift mutations in genes for eIF2Bepsilon or eIF2Bbeta lead to truncated polypeptides that fail to form complexes with the other subunits and are effectively null mutations. Certain point mutations also impair the ability of eIF2Bbeta or -epsilon to form eIF2B holocomplexes and also diminish the intrinsic nucleotide exchange activity of eIF2B. A point mutation in the catalytic domain of e1F2Bepsilon impairs its ability to bind the substrate, while two mutations in eIF2Bbeta actually enhance eIF2 binding. We provide evidence that expression of VWM mutant eIF2B may enhance the translation of specific mRNAs. The variability of the clinical phenotype in VWM may reflect the multiple ways in which VWM mutations affect eIF2B function.