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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Functional Significance of Point Mutations in Stress Chaperone Mortalin and Their Relevance to Parkinson Disease
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Functional Significance of Point Mutations in Stress Chaperone Mortalin and Their Relevance to Parkinson Disease

机译：应激伴侣护胃素中点突变的功能意义及其与帕金森病的相关性

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摘要

Mortalin/mtHsp70/Grp75 (mot-2), a heat shock protein 70 family member, is an essential chaperone, enriched in cancers, and has been shown to possess pro-proliferative and anti-apoptosis functions. An allelic form of mouse mortalin (mot-1) that differs by two amino acids, M618V and G624R, in the C terminus substrate-binding domain has been reported. Furthermore, genome sequencing of mortalin from Parkinson disease patients identified two missense mutants, R126W and P509S. In the present study, we investigated the significance of these mutations in survival, proliferation, and oxidative stress tolerance in human cells. Using mot-1 and mot-2 recombinant proteins and specific antibodies, we performed screening to find their binding proteins and then identified ribosomal protein L-7 (RPL-7) and elongation factor-1 α (EF-1α), which differentially bind to mot-1 and mot-2, respectively. We demonstrate that mot-1, R126W, or P509S mutant (i) lacks mot-2 functions involved in carcinogenesis, such as p53 inactivation and hTERT/hnRNP-K (heterogeneous nuclear ribonucleoprotein K) activation; (ii) causes increased level of endogenous oxidative stress; (iii) results in decreased tolerance of cells to exogenous oxidative stress; and (iv) shows differential binding and impact on the RPL-7 and EF-1α proteins. These factors may mediate the transformation of longevity/pro-proliferative function of mot-2 to the premature aging/anti-proliferative effect of mutants, and hence may have significance in cellular aging, Parkinson disease pathology, and prognosis.
机译：Mortalin / mtHsp70 / Grp75（mot-2）是一种热休克蛋白70家族成员，是必需的伴侣蛋白，富含癌症，已被证明具有促增殖和抗凋亡的功能。据报道，小鼠的mortalin（mot-1）的等位基因形式在C末端底物结合域中相差两个氨基酸M618V和G624R。此外，来自帕金森氏病患者的莫他林的基因组测序鉴定出两个错义突变体R126W和P509S。在本研究中，我们调查了这些突变在人类细胞存活，增殖和氧化应激耐受性中的重要性。我们使用mot-1和mot-2重组蛋白以及特异性抗体，进行筛选以找到它们的结合蛋白，然后鉴定出差异结合的核糖体蛋白L-7（RPL-7）和延伸因子-1α（EF-1α）。分别为mot-1和mot-2。我们证明mot-1，R126W或P509S突变体（i）缺乏参与癌变的mot-2功能，例如p53失活和hTERT / hnRNP-K（异质核糖核蛋白K）激活； （ii）引起内源性氧化应激水平升高； （iii）导致细胞对外源性氧化应激的耐受性降低； （iv）显示了对RPL-7和EF-1α蛋白的不同结合和影响。这些因素可能介导mot-2的寿命/增生功能向突变体的过早衰老/抗增生作用的转化，因此可能在细胞衰老，帕金森氏病的病理和预后中具有重要意义。

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