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Peptidomimetics Based on C-Terminus of Blm10 Stimulate Human 20S Proteasome Activity and Promote Degradation of Proteins
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 s...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221443/ https://www.ncbi.nlm.nih.gov/pubmed/35740902 http://dx.doi.org/10.3390/biom12060777 |
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author | Cekała, Katarzyna Trepczyk, Karolina Sowik, Daria Karpowicz, Przemysław Giełdoń, Artur Witkowska, Julia Giżyńska, Małgorzata Jankowska, Elżbieta Wieczerzak, Ewa |
author_facet | Cekała, Katarzyna Trepczyk, Karolina Sowik, Daria Karpowicz, Przemysław Giełdoń, Artur Witkowska, Julia Giżyńska, Małgorzata Jankowska, Elżbieta Wieczerzak, Ewa |
author_sort | Cekała, Katarzyna |
collection | PubMed |
description | 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 Blm10 activator. Some of the compounds were capable of enhancing the degradation of natively unfolded and oxidatively damaged proteins, such as α-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. |
format | Online Article Text |
id | pubmed-9221443 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-92214432022-06-24 Peptidomimetics Based on C-Terminus of Blm10 Stimulate Human 20S Proteasome Activity and Promote Degradation of Proteins Cekała, Katarzyna Trepczyk, Karolina Sowik, Daria Karpowicz, Przemysław Giełdoń, Artur Witkowska, Julia Giżyńska, Małgorzata Jankowska, Elżbieta Wieczerzak, Ewa Biomolecules Article 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 Blm10 activator. Some of the compounds were capable of enhancing the degradation of natively unfolded and oxidatively damaged proteins, such as α-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. MDPI 2022-06-02 /pmc/articles/PMC9221443/ /pubmed/35740902 http://dx.doi.org/10.3390/biom12060777 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Cekała, Katarzyna Trepczyk, Karolina Sowik, Daria Karpowicz, Przemysław Giełdoń, Artur Witkowska, Julia Giżyńska, Małgorzata Jankowska, Elżbieta Wieczerzak, Ewa Peptidomimetics Based on C-Terminus of Blm10 Stimulate Human 20S Proteasome Activity and Promote Degradation of Proteins |
title | Peptidomimetics Based on C-Terminus of Blm10 Stimulate Human 20S Proteasome Activity and Promote Degradation of Proteins |
title_full | Peptidomimetics Based on C-Terminus of Blm10 Stimulate Human 20S Proteasome Activity and Promote Degradation of Proteins |
title_fullStr | Peptidomimetics Based on C-Terminus of Blm10 Stimulate Human 20S Proteasome Activity and Promote Degradation of Proteins |
title_full_unstemmed | Peptidomimetics Based on C-Terminus of Blm10 Stimulate Human 20S Proteasome Activity and Promote Degradation of Proteins |
title_short | Peptidomimetics Based on C-Terminus of Blm10 Stimulate Human 20S Proteasome Activity and Promote Degradation of Proteins |
title_sort | peptidomimetics based on c-terminus of blm10 stimulate human 20s proteasome activity and promote degradation of proteins |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221443/ https://www.ncbi.nlm.nih.gov/pubmed/35740902 http://dx.doi.org/10.3390/biom12060777 |
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