RESUMEN
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 ß-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.
Asunto(s)
Amiloide/metabolismo , Proteínas de Unión al ADN/metabolismo , Cuerpos de Inclusión/metabolismo , Amiloide/genética , Animales , Caenorhabditis elegans , Proteínas de Unión al ADN/genética , Diseño de Fármacos , Células HeLa , Secuencias Hélice-Giro-Hélice , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Cuerpos de Inclusión/genética , Cuerpos de Inclusión/patología , Estructura Terciaria de Proteína , Proteinopatías TDP-43/tratamiento farmacológico , Proteinopatías TDP-43/genética , Proteinopatías TDP-43/metabolismo , Proteinopatías TDP-43/patologíaRESUMEN
Ambient water nanofilms confined on solid surfaces usually show properties not seen in bulk and play unique roles in many important processes. Here we report diffusion and self-assembly of peptides in ambient water nanofilms on mica, based on "drying microcontact printing" and ex situ atomic force microscopy imaging. We found that diffusion and self-assembly of several peptides in the water nanofilms on mica resulted in one-dimensional "epitaxial" nanofilaments. The peptide self-assembly process is sensitive to the amount of water on the surface, and different peptides with varied molecular structures show different humidity-dependent behaviors. In addition, some peptides that cannot form nanofilaments on substrates in bulk water can be successfully self-assembled into nanofilaments in the water nanofilm.