期刊
FEBS JOURNAL
卷 287, 期 12, 页码 2449-2467出版社
WILEY
DOI: 10.1111/febs.15159
关键词
amyloid; amyotrophic lateral sclerosis; frontotemporal dementia; solid-state NMR; TDP-43
资金
- European Research Council (ERC-2015-StG) [639020]
- IdEx Bordeaux (Chaire d'Installation) [ANR-10-IDEX-03-02]
- ANR [ANR-14-CE09-0020-01]
- Swiss National Science Foundation [P2EZP2_184258]
- CNRS (IR-RMN FR3050)
- Swiss National Science Foundation (SNF) [P2EZP2_184258] Funding Source: Swiss National Science Foundation (SNF)
- European Research Council (ERC) [639020] Funding Source: European Research Council (ERC)
- Agence Nationale de la Recherche (ANR) [ANR-14-CE09-0020] Funding Source: Agence Nationale de la Recherche (ANR)
The TAR DNA-binding protein (TDP-43) self-assembles into prion-like aggregates considered to be the structural hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. Here, we use a combination of electron microscopy, X-ray fiber diffraction, Fourier-transform infrared spectroscopy analysis, and solid-state NMR spectroscopy to investigate the molecular organization of different TDP constructs, namely the full-length TDP-43 (1-414), two C-terminal fragments [TDP-35 (90-414) and TDP-16 (267-414)], and a C-terminal truncated fragment (TDP-43 increment GaroS2), in their fibrillar state. Although the different protein constructs exhibit similar fibril morphology and a typical cross-beta signature by X-ray diffraction, solid-state NMR indicates that TDP-43 and TDP-35 share the same polymorphic molecular structure, while TDP-16 encompasses a well-ordered amyloid core. We identified several residues in the so-called C-terminal GaroS2 (368-414) domain that participates in the rigid core of TDP-16 fibrils, underlining its importance during the aggregation process. Our findings demonstrate that C-terminal fragments can adopt a different molecular conformation in isolation or in the context of the full-length assembly, suggesting that the N-terminal domain and RRM domains play an important role in the TDP-43 amyloid transition.
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