Sandelin Erik, Nordlund Anna, Andersen Peter M, Marklund Stefan S L, Oliveberg Mikael
Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden.
J Biol Chem. 2007 Jul 20;282(29):21230-6. doi: 10.1074/jbc.M700765200. Epub 2007 May 18.
We provide bioinformatical evidence that protein charge plays a key role in the disease mechanism of amyotrophic lateral sclerosis (ALS). Analysis of 100 ALS-associated mutations in copper/zinc superoxide dismutase (SOD1) shows that these are site-selective with a preference to decrease the proteins' net repulsive charge. For each SOD1 monomer this charge is normally -6. Because biomolecules as a rule maintain net negative charge to assure solubility in the cellular interior, the result lends support to the hypothesis of protein aggregation as an initiating event in the ALS pathogenesis. The strength of the preferential reduction of repulsive charge is higher in SOD1-associated ALS than in other inherited protein disorders.
我们提供了生物信息学证据，证明蛋白质电荷在肌萎缩侧索硬化症（ALS）的发病机制中起关键作用。对铜/锌超氧化物歧化酶（SOD1）中100个与ALS相关的突变进行分析表明，这些突变具有位点选择性，倾向于降低蛋白质的净排斥电荷。对于每个SOD1单体，这种电荷通常为-6。由于生物分子通常保持净负电荷以确保在细胞内部的溶解性，这一结果支持了蛋白质聚集作为ALS发病机制起始事件的假说。与SOD1相关的ALS中排斥电荷优先减少的强度高于其他遗传性蛋白质疾病。
