Lin Yi, Mori Eiichiro, Kato Masato, Xiang Siheng, Wu Leeju, Kwon Ilmin, McKnight Steven L
Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
Department of Anatomy and Cell Biology Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, Korea.
Cell. 2016 Oct 20;167(3):789-802.e12. doi: 10.1016/j.cell.2016.10.003.
Two complementary approaches were used in search of the intracellular targets of the toxic PR poly-dipeptide encoded by the repeat sequences expanded in the C9orf72 form of amyotrophic lateral sclerosis. The top categories of PR-bound proteins include constituents of non-membrane invested cellular organelles and intermediate filaments. PR targets are enriched for the inclusion of low complexity (LC) sequences. Evidence is presented indicating that LC sequences represent the direct target of PR binding and that interaction between the PR poly-dipeptide and LC domains is polymer-dependent. These studies indicate that PR-mediated toxicity may result from broad impediments to the dynamics of cell structure and information flow from gene to message to protein.
采用了两种互补方法来寻找由肌萎缩侧索硬化症C9orf72形式中扩增的重复序列所编码的毒性PR多聚二肽的细胞内靶点。与PR结合的蛋白质的主要类别包括非膜包裹细胞器的成分和中间丝。PR靶点富含低复杂性（LC）序列。有证据表明，LC序列是PR结合的直接靶点，并且PR多聚二肽与LC结构域之间的相互作用是聚合物依赖性的。这些研究表明，PR介导的毒性可能源于对细胞结构动态以及从基因到信使再到蛋白质的信息流的广泛阻碍。
