title: Toxic PR Poly-Dipeptides Encoded by the C9orf72 Repeat Expansion Target LC Domain Polymers.
abstract: 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 PRn-bound proteins include constituents of non-membrane invested cellular organelles and intermediate filaments. PRntargets are enriched for the inclusion of low complexity (LC) sequences. Evidence is presented indicating that LC sequences represent the direct target of PRnbinding and that interaction between the PRnpoly-dipeptide and LC domains is polymer-dependent. These studies indicate that PRn-mediated toxicity may result from broad impediments to the dynamics of cell structure and information flow from gene to message to protein.
authors: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
authors: Yi
authors: Y
authors: Lin
authors: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
authors: Eiichiro
authors: E
authors: Mori
authors: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
authors: Masato
authors: M
authors: Kato
authors: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
authors: Siheng
authors: S
authors: Xiang
authors: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
authors: Leeju
authors: L
authors: Wu
authors: Department of Anatomy and Cell Biology Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, Korea. Electronic address: ilmin.kwon@skku.edu.
authors: Ilmin
authors: I
authors: Kwon
authors: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. Electronic address: steven.mcknight@utsouthwestern.edu.
authors: Steven L
authors: SL
authors: McKnight
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion; D004151:Dipeptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072417:Protein Domains; D011506:Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004151:Dipeptides; D007381:Intermediate Filament Proteins; D010455:Peptides; D011506:Proteins; C011083:polyproline; C015462:polyarginine
keywords: 1,6-hexanediol; C9orf72; amyloid-like polymers; cellular puncta not invested by surrounding membranes; intermediate filaments; labile; low complexity sequence polymers; toxic PRn and GRn poly-dipeptides