Non-canonical α-methyl amino acids were incorporated at various sites in the sequence of intrinsically disordered activation domain from the p160 transcriptional co-activator (ACTR) to facilitate the formation of α-helical structures. Kinetic and thermodynamic data confirm the induced fit mechanism of complex formation between the synthesized ACTR variants and the nuclear co-activator binding domain (NCBD).
The nuclear coactivator binding domain (NCBD) of transcriptional co-regulator CREB-binding protein (CBP) is an example of conformationallym alleable proteins 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 pathwayt hat resultsi np rotein aggregation and selfassembly into amyloid fibers. The initial steps of such protein misfolding are driven by intermolecular interactions of its N-terminal a-helix bringing multiple NCBD molecules into contact. These oligomers then undergo slow but progressive interconversion into b-sheet-containing aggregates.T o reveal the concealed aggregation potentialo fN CBD we used ac hemically 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 b-sheet structures. The unexpecteda ggregation of NCBD needs to be taken into considerationg iven the multitude of protein-protein interactions and resulting biological functions mediated by CBP.
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