Structural analysis of disease-related TDP-43 D169G mutation: Linking enhanced stability and caspase cleavage efficiency to protein accumulation

Chien Hao Chiang, Cédric Grauffel, Lien Szu Wu, Pan Hsien Kuo, Lyudmila G. Doudeva, Carmay Lim, Che Kun James Shen, Hanna S. Yuan

研究成果: 雜誌貢獻文章同行評審

40 引文 斯高帕斯(Scopus)

摘要

The RNA-binding protein TDP-43 forms intracellular inclusions in amyotrophic lateral sclerosis (ALS). While TDP-43 mutations have been identified in ALS patients, how these mutations are linked to ALS remains unclear. Here we examined the biophysical properties of six ALS-linked TDP-43 mutants and found that one of the mutants, D169G, had higher thermal stability than wild-type TDP-43 and that it was cleaved by caspase 3 more efficiently, producing increased levels of the C-terminal 35 kD fragments (TDP-35) in vitro and in neuroblastoma cells. The crystal structure of the TDP-43 RRM1 domain containing the D169G mutation in complex with DNA along with molecular dynamics simulations reveal that the D169G mutation induces a local conformational change in a β turn and increases the hydrophobic interactions in the RRM1 core, thus enhancing the thermal stability of the RRM1 domain. Our results provide the first crystal structure of TDP-43 containing a disease-linked D169G mutation and a disease-related mechanism showing that D169G mutant is more susceptible to proteolytic cleavage by caspase 3 into the pathogenic C-terminal 35-kD fragments due to its increased stability in the RRM1 domain. Modulation of TDP-43 stability and caspase cleavage efficiency could present an avenue for prevention and treatment of TDP-43-linked neurodegeneration.
原文英語
文章編號21581
期刊Scientific Reports
6
DOIs
出版狀態已發佈 - 二月 17 2016
對外發佈

ASJC Scopus subject areas

  • 多學科

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