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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...

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Autores principales: Cekała, Katarzyna, Trepczyk, Karolina, Sowik, Daria, Karpowicz, Przemysław, Giełdoń, Artur, Witkowska, Julia, Giżyńska, Małgorzata, Jankowska, Elżbieta, Wieczerzak, Ewa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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