Chen Yiwen, Dokholyan Nikolay V
Mol Biol Evol. 2008 Aug;25(8):1530-3. doi: 10.1093/molbev/msn122. Epub 2008 May 23.
Protein aggregation is the phenomenon of protein self-association potentially leading to detrimental effects on physiology, which is closely related to numerous human diseases such as Alzheimer's and Parkinson's disease. Despite progress in understanding the mechanism of protein aggregation, how natural selection against protein aggregation acts on subunits of protein complexes and on proteins with different contributions to organism fitness remains largely unknown. Here, we perform a proteome-wide analysis by using an experimentally validated algorithm TANGO and utilizing sequence, interactomic and phenotype-based functional genomic data from yeast, fly, and nematode. We find that proteins that are capable of forming homooligomeric complex have lower aggregation propensity compared with proteins that do not function as homooligomer. Further, proteins that are essential to the fitness of an organism have lower aggregation propensity compared with nonessential ones. Our finding suggests that the selection force against protein aggregation acts across different hierarchies of biological system.
蛋白质聚集是蛋白质自我缔合的现象，可能对生理机能产生有害影响，它与许多人类疾病密切相关，如阿尔茨海默病和帕金森病。尽管在理解蛋白质聚集机制方面取得了进展，但针对蛋白质聚集的自然选择如何作用于蛋白质复合物的亚基以及对生物体适应性有不同贡献的蛋白质，在很大程度上仍然未知。在这里，我们通过使用经过实验验证的算法TANGO，并利用来自酵母、果蝇和线虫的基于序列、相互作用组学和表型的功能基因组数据，进行了全蛋白质组分析。我们发现，与不能形成同聚体的蛋白质相比，能够形成同聚体复合物的蛋白质具有较低的聚集倾向。此外，与非必需蛋白质相比，对生物体适应性至关重要的蛋白质具有较低的聚集倾向。我们的发现表明，针对蛋白质聚集的选择力在生物系统的不同层次上发挥作用。
