Aggregation and Amyloidogenicity of the Nuclear Coactivator Binding Domain of CREB‐Binding Protein. Issue 44 (14th July 2020)

• Record Type: Journal Article
• Authors: Garcia, Ana Maria; Giorgiutti, Christophe; El Khoury, Youssef; Bauer, Valentin; Spiegelhalter, Coralie; Leize‐Wagner, Emmanuelle; Hellwig, Petra; Potier, Noelle; Torbeev, Vladimir
• Is Part Of: Chemistry. Volume 26:Issue 44(2020)
• Page Start: 9889
• Page End: 9899
• Publication Date: 2020-07-14
• Subjects: amyloid beta-peptides -- conformation analysis -- protein folding -- self-assembly -- transcription coactivators; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202001847
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: The nuclear coactivator binding domain (NCBD) of transcriptional co‐regulator CREB‐binding protein (CBP) is an example of conformationally malleable 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 pathway that 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 into contact. These oligomers then undergo slow but progressive interconversion into β‐sheet‐containing aggregates. To reveal the concealed aggregation potential of NCBD we used a 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 the multitude of protein–protein interactions and resulting biological functions mediated by CBP. Abstract : Self assembled with a mirror : The self‐assembly of nuclear coactivator binding domain (NCBD) into oligomers and amyloid fibers is reported. The initial oligomerization is mediated through an N‐terminal helical fragment. Subsequently, the oligomers interconvert towards more stable β‐sheet structures through a process that is facilitated by the presence of a mirror‐image d ‐NCBD construct.