The truncated C-terminal RNA recognition motif of TDP-43 protein plays a key role in forming proteinaceous aggregates

Yi Ting Wang, Pan Hsien Kuo, Chien Hao Chiang, Jhe Ruei Liang, Yun Ru Chen, Shuying Wang, James C.K. Shen, Hanna S. Yuan

Research output: Contribution to journalArticlepeer-review

82 Citations (Scopus)


TDP-43 is the major pathological protein identified in the cellular inclusions in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The pathogenic forms of TDP-43 are processed C-terminal fragments containing a truncated RNA-recognition motif (RRM2) and a glycine-rich region. Although extensive studies have focused on this protein, it remains unclear how the dimeric full-length TDP-43 is folded and assembled and how the processed C-terminal fragments are misfolded and aggregated. Here, using size-exclusion chromatography, pulldown assays, and small angle x-ray scattering, we show that the C-terminal-deleted TDP-43 without the glycinerich tail is sufficient to form a head-to-head homodimer primarily via its N-terminal domain. The truncated RRM2, as well as twoβ-strands within the RRM2, form fibrils in vitro with a similar amyloid-negative staining property to those of TDP-43 pathogenic fibrils in diseases. In addition to the glycine-rich region, the truncated RRM2, but not the intact RRM2, plays a key role in forming cytoplasmic inclusions in neuronal cells. Our data thus suggest that the process that disrupts the dimeric structure, such as the proteolytic cleavage of TDP-43 within the RRM2 that removes the N-terminal dimerization domain, may produce unassembled truncated RRM2 fragments with abnormally exposedβ-strands, which can oligomerize into high-order inclusions.

Original languageEnglish
Pages (from-to)9049-9057
Number of pages9
JournalJournal of Biological Chemistry
Issue number13
Publication statusPublished - Mar 29 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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