title: Structural transformation of the amyloidogenic core region of TDP-43 protein initiates its aggregation and cytoplasmic inclusion.
abstract: TDP-43 (TAR DNA-binding protein of 43 kDa) is a major deposited protein in amyotrophic lateral sclerosis and frontotemporal dementia with ubiquitin. A great number of genetic mutations identified in the flexible C-terminal region are associated with disease pathologies. We investigated the molecular determinants of TDP-43 aggregation and its underlying mechanisms. We identified a hydrophobic patch (residues 318-343) as the amyloidogenic core essential for TDP-43 aggregation. Biophysical studies demonstrated that the homologous peptide formed a helix-turn-helix structure in solution, whereas it underwent structural transformation from an α-helix to a β-sheet during aggregation. Mutation or deletion of this core region significantly reduced the aggregation and cytoplasmic inclusions of full-length TDP-43 (or TDP-35 fragment) in cells. Thus, structural transformation of the amyloidogenic core initiates the aggregation and cytoplasmic inclusion formation of TDP-43. This particular core region provides a potential therapeutic target to design small-molecule compounds for mitigating TDP-43 proteinopathies.
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Jiang
authors.forename: Mei-Xia
authors.initials: MX
authors.lastname: Che
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.forename: Chen-Jie
authors.initials: CJ
authors.lastname: Zhou
authors.forename: Mu-Yun
authors.initials: MY
authors.lastname: Xie
authors.forename: Hai-Yin
authors.initials: HY
authors.lastname: Li
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: He
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Hu
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D006367:HeLa Cells; D019077:Helix-Turn-Helix Motifs; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D057177:TDP-43 Proteinopathies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D000682:Amyloid; D004268:DNA-Binding Proteins
keywords: Aggregation; Amyloid; Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease); Circular Dichroism (CD); Fluorescence; Hydrophobic Patch; Inclusion Formation; NMR; Structural Transformation; TDP-43