期刊
PLOS ONE
卷 8, 期 10, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0076629
关键词
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资金
- Fundacao para a Ciencia e a Tecnologia (FCT/MCTES, Portugal) [PTDC/EBB-BIO/117793/2010, PTDC/QUIBIQ/117789/2010, SFRH/BD/31126/2006, B017/BI-BI/2012, SFRH/BPD/47477/2008, PEst-OE/EQB/LA0004/2011]
- Liga Portuguesa contra o Cancro - LPCC-NRS (Portugal)
- Heisenberg fellowship of the Deutsche Forschungsgemeinschaft [FR 1488/3-2]
- Fundação para a Ciência e a Tecnologia [PTDC/EBB-BIO/117793/2010, SFRH/BPD/47477/2008, SFRH/BD/31126/2006] Funding Source: FCT
S100 proteins are small dimeric calcium-binding proteins which control cell cycle, growth and differentiation via interactions with different target proteins. Intrinsic disorder is a hallmark among many signaling proteins and S100 proteins have been proposed to contain disorder-prone regions. Interestingly, some S100 proteins also form amyloids: S100A8/A9 forms fibrils in prostatic inclusions and S100A6 fibrillates in vitro and seeds SOD1 aggregation. Here we report a study designed to investigate whether beta-aggregation is a feature extensive to more members of S100 family. In silico analysis of seven human S100 proteins revealed a direct correlation between aggregation and intrinsic disorder propensity scores, suggesting a relationship between these two independent properties. Averaged position-specific analysis and structural mapping showed that disorder-prone segments are contiguous to aggregation-prone regions and that whereas disorder is prominent on the hinge and target protein-interaction regions, segments with high aggregation propensity are found in ordered regions within the dimer interface. Acidic conditions likely destabilize the seven S100 studied by decreasing the shielding of aggregation-prone regions afforded by the quaternary structure. In agreement with the in silico analysis, hydrophobic moieties become accessible as indicated by strong ANS fluorescence. ATR-FTIR spectra support a structural inter-conversion from alpha-helices to intermolecular beta-sheets, and prompt ThT-binding takes place with no noticeable lag phase. Dot blot analysis using amyloid conformational antibodies denotes a high diversity of conformers; subsequent analysis by TEM shows fibrils as dominant species. Altogether, our data suggests that beta-aggregation and disorder-propensity are related properties in S100 proteins, and that the onset of aggregation is likely triggered by loss of protective tertiary and quaternary interactions.
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