title: BRICHOS binds to a designed amyloid-forming β-protein and reduces proteasomal inhibition and aggresome formation.
abstract: 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.
authors.affiliation: Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Novum 5th floor, 141 57 Huddinge, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Dolfe
authors.affiliation: Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Novum 5th floor, 141 57 Huddinge, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.affiliation: Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Novum 5th floor, 141 57 Huddinge, Sweden Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Box 7011, 750 07 Uppsala, Sweden Institute of Mathematics and Natural Sciences, Tallinn University, Narva mnt 25, 101 20 Tallinn, Estonia.
authors.forename: Jan
authors.initials: J
authors.lastname: Johansson
authors.affiliation: Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Novum 5th floor, 141 57 Huddinge, Sweden jenny.presto@ki.se.
authors.forename: Jenny
authors.initials: J
authors.lastname: Presto
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000378:metabolism; D066329:Protein Aggregates / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; C499960:ITM2C protein, human; D008565:Membrane Proteins; D061988:Proteasome Inhibitors; D066329:Protein Aggregates; D046988:Proteasome Endopeptidase Complex
keywords: Alzheimer's disease; BRICHOS; amyloid; molecular chaperone; protein conformation; protein inclusions