BRICHOS binds to a designed amyloid-forming β-protein and reduces proteasomal inhibition and aggresome formation

• Published in: Biochemical journal Vol. 473; no. 2; p. 167
• Main Authors: Dolfe, Lisa, Winblad, Bengt, Johansson, Jan, Presto, Jenny
• Format: Journal Article
• Language: English
• Published: England 15-01-2016
• Subjects: Amino Acid Sequence; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Cell Survival - physiology; HEK293 Cells; Humans; Membrane Proteins - genetics; Membrane Proteins - metabolism; Molecular Sequence Data; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - metabolism; Protein Aggregates - physiology; Protein Binding - physiology; protein conformation; molecular chaperone; protein inclusions; amyloid; Alzheimer's disease; BRICHOS
• ISSN: 1470-8728
• DOI: 10.1042/BJ20150920

The BRICHOS domain is associated with proliferative, degenerative and amyloid diseases, and it has been shown to inhibit fibril formation and toxicity of the Alzheimer's disease-associated amyloid β-peptide. ProSP-C (prosurfactant protein C) BRICHOS binds to stretches of hydrophobic amino acid residues, which are unfolded or in β-strand conformation, suggesting that it may have broad anti-amyloid activity. We have studied the effect of the proSP-C BRICHOS domain on the designed amyloidogenic β-sheet proteins β17 and β23. β17 expressed in the secretory pathway of HEK (human embryonic kidney)-293 cells forms intracellular inclusions, whereas β23 is rapidly degraded. Co-expression of BRICHOS leads to a reduction in β17 inclusion size and increased levels of soluble β17 and β23. Furthermore, BRICHOS interacts with the β-proteins intracellularly, reduces their ubiquitination and decreases aggresome formation and proteasomal inhibition. Collectively, these data suggest that BRICHOS is capable of delaying the aggregation process and toxicity of amyloidogenic proteins in a generic manner.