Brown C R, Hong-Brown L Q, Welch W J
Department of Medicine, The University of California, San Francisco 94143, USA.
J Bioenerg Biomembr. 1997 Oct;29(5):491-502. doi: 10.1023/a:1022491124939.
Many human diseases arise as a result of mutations within genes encoding essential proteins. In many cases, the mutations are not so severe as to render the protein biologically inactive. Rather, the mutations oftentimes result in only subtle protein-folding abnormalities. In the case of the CFTR protein, a mutation leading to the loss of a single amino acid is responsible for the diseased state in the majority of individuals with cystic fibrosis. Here the newly synthesized mutant CFTR protein, missing a phenylalanine residue at position 508 (delta F508 CFTR), is unable to transit from the endoplasmic reticulum to the plasma membrane, where it functions as a regulator of chloride transport. All of the available evidence indicate that the newly synthesized delta F508 CFTR protein adopts a slightly altered conformation and therefore is retained at the level of the endoplasmic reticulum, ostensibly by the actions of the cellular quality control system. Because the mutant protein is capable of functioning as a chloride channel, developing ways to elicit its release out of the ER and to the plasma membrane has important clinical implications. Herein, we discuss our recent studies showing that the protein-folding defect associated with the delta F508 CFTR mutation, as well as a number of other temperature-sensitive mutations, can be overcome by strategies designed to influence protein folding inside the cell. Specifically we show that a number of low-molecular-weight compounds, all of which are known to stabilize proteins in their native conformation, are effective in rescuing the folding and/or processing defects associated with different mutations that oftentimes lead to human disease.
许多人类疾病是由编码必需蛋白质的基因突变引起的。在许多情况下，这些突变并不严重到使蛋白质失去生物学活性。相反，这些突变通常只会导致细微的蛋白质折叠异常。就囊性纤维化跨膜传导调节因子（CFTR）蛋白而言，导致单个氨基酸缺失的突变是大多数囊性纤维化患者患病状态的原因。在这里，新合成的突变型CFTR蛋白在第508位缺失一个苯丙氨酸残基（ΔF508 CFTR），无法从内质网转运到质膜，而它在质膜上作为氯离子转运的调节因子发挥作用。所有现有证据表明，新合成的ΔF508 CFTR蛋白采用了略有改变的构象，因此显然通过细胞质量控制系统的作用被保留在内质网水平。由于突变蛋白能够作为氯离子通道发挥作用，开发使其从内质网释放到质膜的方法具有重要的临床意义。在此，我们讨论我们最近的研究，这些研究表明，与ΔF508 CFTR突变以及其他一些温度敏感突变相关的蛋白质折叠缺陷，可以通过旨在影响细胞内蛋白质折叠的策略来克服。具体而言，我们表明一些低分子量化合物，所有这些化合物都已知能稳定蛋白质的天然构象，在挽救与不同突变相关的折叠和/或加工缺陷方面是有效的，这些突变常常导致人类疾病。
