title: Characterization of β-domains in C-terminal fragments of TDP-43 by scanning tunneling microscopy.
abstract: The TAR DNA-binding protein 43 (TDP-43) has been identified as a critical player in a range of neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Recent discoveries demonstrate the important role of carboxyl-terminal fragments of TDP-43 in its proteinopathy. Herein, we report the characterization of β-domains in the C-terminal fragments of TDP-43 using scanning tunneling microscopy (STM). Careful comparison of the wild-type TDP-43 (Wt) and the three mutant TDP-43 peptides: an ALS-related mutant peptide: phosphorylated A315T mutant TDP-43 (A315T(p)) and two model peptides: A315T mutant TDP-43 (A315T), A315E mutant TDP-43 (A315E) reveals that A315T(p) has a longer core region of the β-domain than Wt. A315E possesses the longest core region of the β-domain and A315T(p) mutant TDP-43 has the second longest core region of the β-domain. The core regions of the β-domains for A315T and Wt TDP-43 have the same length. This observation provides a supportive evidence of a higher tendency in beta-sheet formation of A315T(p) containing TDP-43 fragment, and structural mechanism for the higher cytotoxicity and accelerated fibril formation of the A315T(p) mutation-containing TDP-43 peptide as compared with Wt TDP-43.
authors.affiliation: Key Laboratory for Biological Effects of Nanomaterials and Nanosafety (Chinese Academy of Sciences), National Center for Nanoscience and Technology, Beijing 100190, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Jianghong
authors.initials: J
authors.lastname: Liu
authors.forename: Yanlian
authors.initials: Y
authors.lastname: Yang
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Wu
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D006801:Humans; D016252:Microscopy, Scanning Tunneling; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000737:chemistry*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D000682:Amyloid; D004268:DNA-Binding Proteins; D010446:Peptide Fragments