Characterization of β-domains in C-terminal fragments of TDP-43 by scanning tunneling microscopy

Meng Xu, Li Zhu, Jianghong Liu, Yanlian Yang*, Jane Y. Wu, Chen Wang

*Corresponding author for this work

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)11-16
Number of pages6
JournalJournal of Structural Biology
Volume181
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • Amyloid
  • Fibril formation
  • STM
  • TAR DNA-binding protein 43
  • β-Domain

ASJC Scopus subject areas

  • Structural Biology

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