Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisboa, Portugal.
PLoS One. 2011;6(6):e20854. doi: 10.1371/journal.pone.0020854. Epub 2011 Jun 9.
Protein conformational disorders are associated with the appearance, persistence, accumulation, and misprocessing of aberrant proteins in the cell. The etiology of renal tubular dysgenesis (RTD) is linked to mutations in the angiotensin-converting enzyme (ACE). Here, we report the identification of a novel ACE mutation (Q1069R) in an RTD patient. ACE Q1069R is found sequestered in the endoplasmic reticulum and is also subject to increased proteasomal degradation, preventing its transport to the cell surface and extracellular fluids. Modulation of cellular proteostasis by temperature shift causes an extension in the processing time and trafficking of ACE Q1069R resulting in partial rescue of the protein processing defect and an increase in plasma membrane levels. In addition, we found that temperature shifting causes the ACE Q1069R protein to be secreted in an active state, suggesting that the mutation does not affect the enzyme's catalytic properties.
蛋白质构象疾病与细胞中异常蛋白质的出现、持续存在、积累和错误处理有关。肾单位发育不全（RTD）的病因与血管紧张素转换酶（ACE）的突变有关。在这里，我们报告了在一名 RTD 患者中鉴定出一种新型 ACE 突变（Q1069R）。ACE Q1069R 被隔离在内质网中，并且还受到增加的蛋白酶体降解的影响，从而阻止其转运到细胞表面和细胞外液中。通过温度转换对细胞内蛋白质稳态的调节导致 ACE Q1069R 的加工时间和运输延长，从而部分挽救了蛋白质加工缺陷，并增加了质膜水平。此外，我们发现温度转换会导致 ACE Q1069R 蛋白以活性状态分泌，表明该突变不影响酶的催化特性。
