title: Molecular mechanism of oxidation-induced TDP-43 RRM1 aggregation and loss of function.
abstract: Cysteine oxidation of the two RNA recognition motifs (RRM1 and RRM2) of TDP-43, a multi-domain protein involved in neurodegenerative diseases, results in loss of function and accumulation of insoluble aggregates under both in vitro and in vivo conditions. However, the molecular mechanisms linking cysteine oxidation to protein aggregation and functional aberration remain unknown. We report that oxidation of cysteines in RRM1, but not in other domains, induced conformational changes which subsequently resulted in protein aggregation and loss of nucleic acid-binding activity. Thus, oxidation-induced conformational change of RRM1 plays a key role in TDP-43 aggregation and disease progression.
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors: Chung-ke
authors: CK
authors: Chang
authors: Ming-hui
authors: MH
authors: Chiang
authors: Elsie Khai-Woon
authors: EK
authors: Toh
authors: Chi-Fon
authors: CF
authors: Chang
authors: Tai-huang
authors: TH
authors: Huang
mesh_terms: D000595:Amino Acid Sequence; D017124:Conserved Sequence; D003545:Cysteine / Q000737:chemistry* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010084:Oxidation-Reduction; D011489:Protein Denaturation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D011994:Recombinant Proteins; D003545:Cysteine