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


ABSTRACT: 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 glycine-rich tail is sufficient to form a head-to-head homodimer primarily via its N-terminal domain. The truncated RRM2, as well as two ?-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 exposed ?-strands, which can oligomerize into high-order inclusions.

SUBMITTER: Wang YT 

PROVIDER: S-EPMC3610977 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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

Wang Yi-Ting YT   Kuo Pan-Hsien PH   Chiang Chien-Hao CH   Liang Jhe-Ruei JR   Chen Yun-Ru YR   Wang Shuying S   Shen James C K JC   Yuan Hanna S HS  

The Journal of biological chemistry 20130131 13


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 aggregat  ...[more]

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