BIBLIOS

Document type
Journal articles

Document subtype
Full paper

Title
Intrinsically Disordered and Aggregation Prone Regions Underlie ?-Aggregation in S100 Proteins

Participants in the publication
Sofia B. Carvalho (Author)
Hugo M. Botelho (Author)
Sónia S. Leal (Author)
Isabel Cardoso (Author)
Günter Fritz (Author)
Cláudio M. Gomes (Author)
Dep. Química e Bioquímica
BioISI

Summary
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 β-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 α-helices to intermolecular β-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 β-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.


Institution
INSTITUTO DE TECNOLOGIA QUÍMICA E BIOLÓGICA

Where published
PLoS ONE

Publication Identifiers
ISSN - 1932-6203

Publisher
Public Library of Science (PLoS)



Document Identifiers
DOI - https://doi.org/10.1371/journal.pone.0076629
URL - http://dx.doi.org/10.1371/journal.pone.0076629