Journal
BIOMOLECULES
Volume 12, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/biom12060777
Keywords
proteasome; activation; 20S; neurodegenerative diseases; microscale thermophoresis
Categories
Funding
- National Science Center [UMO-2019/33/B/NZ7/00112]
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In this study, we designed and obtained a series of peptidomimetic stimulators of 20S proteasome, which can enhance protein degradation and increase the activity of proteasome in cells. These compounds may have the potential to counteract proteasome impairment in patients with age-related diseases.
Degradation of misfolded, redundant and oxidatively damaged proteins constitutes one of the cellular processes which are influenced by the 20S proteasome. However, its activity is generally thought to decrease with age which leads to the gradual accumulation of abnormal proteins in cells and their subsequent aggregation. Therefore, increasing proteasomal degradation constitutes a promising strategy to delay the onset of various age-related diseases, including neurodegenerative disorders. In this study we designed and obtained a series of peptidomimetic stimulators of 20S comprising in their sequences the C-terminal fragment of B1m10 activator. Some of the compounds were capable of enhancing the degradation of natively unfolded and oxidatively damaged proteins, such as oc-synuclein and enolase, whose applicability as proteasome substrates was evaluated by microscale thermophoresis (MST). Furthermore, they increased the ChT-L activity of the proteasome in HEK293T cell extracts. Our studies indicate that the 20S proteasome-mediated protein substrates hydrolysis may be selectively increased by peptide-based stimulators acting in an allosteric manner. These compounds, after further optimization, may have the potential to counteract proteasome impairment in patients suffering from age-related diseases.
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