Temasek Life Sciences Laboratory and Department of Biological Sciences, National University of Singapore, 1 Research Link, Singapore 117604, Singapore.
Semin Cell Dev Biol. 2010 Jul;21(5):533-9. doi: 10.1016/j.semcdb.2010.02.007. Epub 2010 Feb 21.
During protein synthesis, the orderly progression of folding, modification, and assembly is paramount to function and vis-à-vis cellular viability. Accordingly, sophisticated quality control mechanisms have evolved to monitor protein maturation throughout the cell. Proteins failing at any step are segregated and degraded as a preventative measure against potential toxicity. Although protein quality control is generally poorly understood, recent research advances in endoplasmic reticulum-associated degradation (ERAD) pathways have provided the most detailed view so far. The discovery of distinct substrate processing sites established a biochemical basis for genetic profiles of model misfolded proteins. Detailed mechanisms for substrate recognition were recently uncovered. For some proteins, sequential glycan trimming steps set a time window for folding. Proteins still unfolded at the final stage expose a specific degradation signal recognized by the ERAD machinery. Through this mechanism, the system does not in fact know that a molecule is "misfolded". Instead, it goes by the premise that proteins past due have veered off their normal folding pathways and therefore aberrant.
在蛋白质合成过程中，折叠、修饰和组装的有序进行对功能和细胞活力至关重要。因此，已经进化出复杂的质量控制机制来监测细胞内蛋白质的成熟过程。任何步骤失败的蛋白质都会被隔离和降解，以防止潜在的毒性。尽管蛋白质质量控制通常理解得很差，但内质网相关降解（ERAD）途径的最新研究进展提供了迄今为止最详细的观点。不同底物处理位点的发现为模型错误折叠蛋白质的遗传特征奠定了生化基础。最近发现了底物识别的详细机制。对于一些蛋白质，连续的聚糖修剪步骤为折叠设定了时间窗口。在最后阶段仍未展开的蛋白质会暴露出一个由 ERAD 机制识别的特定降解信号。通过这种机制，系统实际上并不知道一个分子是“错误折叠的”。相反，它的前提是过期的蛋白质已经偏离了正常的折叠途径，因此是异常的。
