Aggregation and amyloidogenicity of nuclear coactivator binding domain of CREB‐binding protein.

: Nuclear coactivator binding domain (NCBD) of transcriptional co-regulator CREB-binding protein (CBP) is an example of conformationally malleable protein that can bind to structurally unrelated protein targets and adopt distinct folds in the respective protein complexes. Here, we show that the folding landscape of NCBD contains an alternative pathway, which results in protein aggregation and self-assembly into amyloid fibers. The initial steps of such protein misfolding are driven by intermolecular interactions of its N-terminal α-helix bringing multiple NCBD molecules in contact. Then, these oligomers undergo slow but progressive interconversion into β-sheet containing aggregates. To reveal the concealed aggregation potential of NCBD we used chemically synthesized mirror-image  D -NCBD form. The addition of  D -NCBD promoted self-assembly into amyloid precipitates presumably due to formation of thermodynamically more stable racemic β-sheet structures. The unexpected aggregation of NCBD needs to be taken into consideration given multitude of protein-protein interactions and resulting biological functions mediated by CBP.