期刊
FASEB JOURNAL
卷 34, 期 1, 页码 365-385出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201901897R
关键词
neurodegenerative diseases; nucleic acid; phase transitions; prions; SELEX
资金
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) [01]
- Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)
- Brown University (Brown), Brazil Initiative Collaboration Grant
Structural conversion of cellular prion protein (PrP (c)) into scrapie PrP (PrPSc) and subsequent aggregation are key events associated with the onset of transmissible spongiform encephalopathies (TSEs). Experimental evidence supports the role of nucleic acids (NAs) in assisting this conversion. Here, we asked whether PrP undergoes liquid-liquid phase separation (LLPS) and if this process is modulated by NAs. To this end, two 25-mer DNA aptamers, A1 and A2, were selected against the globular domain of recombinant murine PrP (rPrP(90-231)) using SELEX methodology. Multiparametric structural analysis of these aptamers revealed that A1 adopts a hairpin conformation. Aptamer binding caused partial unfolding of rPrP(90-231) and modulated its ability to undergo LLPS and fibrillate. In fact, although free rPrP(90-231) phase separated into large droplets, aptamer binding increased the number of droplets but noticeably reduced their size. Strikingly, a modified A1 aptamer that does not adopt a hairpin structure induced formation of amyloid fibrils on the surface of the droplets. We show here that PrP undergoes LLPS, and that the PrP interaction with NAs modulates phase separation and promotes PrP fibrillation in a NA structure and concentration-dependent manner. These results shed new light on the roles of NAs in PrP misfolding and TSEs.
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