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- Johansson, Jan, et al.
(författare)
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BRICHOS binds to a designed amyloid-forming beta-protein and reduces proteasomal inhibition and aggresome formation
- 2016
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Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 473, s. 167-178
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Tidskriftsartikel (refereegranskat)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 beta-peptide. ProSP-C (prosurfactant protein C) BRICHOS binds to stretches of hydrophobic amino acid residues, which are unfolded or in beta-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 beta-sheet proteins beta 17 and beta 23. beta 17 expressed in the secretory pathway of HEK (human embryonic kidney)-293 cells forms intracellular inclusions, whereas beta 23 is rapidly degraded. Co-expression of BRICHOS leads to a reduction in beta 17 inclusion size and increased levels of soluble beta 17 and beta 23. Furthermore, BRICHOS interacts with the beta-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.
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| 2. |
- Johansson, Jan, et al.
(författare)
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Control of amyloid assembly by autoregulation
- 2012
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Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 447, s. 185-192
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Forskningsöversikt (refereegranskat)abstract
- The assembly of proteins into amyloid fibrils can be an element of both protein aggregation diseases and a functional unit in healthy biological pathways. In both cases, it must be kept under tight control to prevent undesired aggregation. In normophysiology, proteins can self-chaperone amyloidogenic segments by restricting their conformational flexibility in an overall stabilizing protein fold. However, some aggregation-prone segments cannot be controlled in this manner and require additional regulatory elements to limit fibrillation. The present review summarizes different molecular mechanisms that proteins use to control their own assembly into fibrils, such as the inclusion of a chaperoning domain or a blocking segment in the proform, the controlled release of an amyloidogenic region from the folded protein, or the adjustment of fibrillation propensity according to pH. Autoregulatory elements can control disease-related as well as functional fibrillar protein assemblies and distinguish a group of self-regulating amyloids across a wide range of biological functions and organisms.
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