4.7 Article

Insight into the Folding and Dimerization Mechanisms of the N-Terminal Domain from Human TDP-43

期刊

出版社

MDPI
DOI: 10.3390/ijms21176259

关键词

amyotrophic lateral sclerosis; folding intermediate; misfolding; self-assembly; neurodegeneration; proteinopathy; native-like state; chevron plot

资金

  1. Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (AriSLA) [TDP-43-STRUCT]
  2. Fondazione Cassa di Risparmio di Firenze [TDP43SLA]

向作者/读者索取更多资源

TAR DNA-binding protein 43 (TDP-43) is a 414-residue long nuclear protein whose deposition into intraneuronal insoluble inclusions has been associated with the onset of amyotrophic lateral sclerosis (ALS) and other diseases. This protein is physiologically a homodimer, and dimerization occurs through the N-terminal domain (NTD), with a mechanism on which a full consensus has not yet been reached. Furthermore, it has been proposed that this domain is able to affect the formation of higher molecular weight assemblies. Here, we purified this domain and carried out an unprecedented characterization of its folding/dimerization processes in solution. Exploiting a battery of biophysical approaches, ranging from FRET to folding kinetics, we identified a head-to-tail arrangement of the monomers within the dimer. We found that folding of NTD proceeds through the formation of a number of conformational states and two parallel pathways, while a subset of molecules refold slower, due to proline isomerism. The folded state appears to be inherently prone to form high molecular weight assemblies. Taken together, our results indicate that NTD is inherently plastic and prone to populate different conformations and dimeric/multimeric states, a structural feature that may enable this domain to control the assembly state of TDP-43.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据