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Protein degradation profile reveals dynamic nature of 20S proteasome small molecule stimulation

Small molecules have been discovered to stimulate the 20S core particle (CP) of the proteasome to degrade proteins. However, the impact a 20S CP stimulator can have on the regulation of protein levels has not been fully characterized. Previous studies have focused on using one kind of stimulator to...

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Detalles Bibliográficos
Autores principales: Coleman, Rachel A., Mohallem, Rodrigo, Aryal, Uma K., Trader, Darci J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: RSC 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341874/
https://www.ncbi.nlm.nih.gov/pubmed/34458805
http://dx.doi.org/10.1039/d0cb00191k
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author Coleman, Rachel A.
Mohallem, Rodrigo
Aryal, Uma K.
Trader, Darci J.
author_facet Coleman, Rachel A.
Mohallem, Rodrigo
Aryal, Uma K.
Trader, Darci J.
author_sort Coleman, Rachel A.
collection PubMed
description Small molecules have been discovered to stimulate the 20S core particle (CP) of the proteasome to degrade proteins. However, the impact a 20S CP stimulator can have on the regulation of protein levels has not been fully characterized. Previous studies have focused on using one kind of stimulator to enhance the degradation of specific 20S CP substrates. We present here a study that utilizes several 20S CP stimulators to determine how each can affect the degradation of proteins in a biochemical assay with purified proteins and of an overexpressed GFP-fusion protein in cells. We also evaluate the effects of two stimulators on the whole cellular proteome in HEK-293T cells using label-free quantitative proteomic analysis for a broader understanding on their impact. Our studies demonstrate that 20S CP stimulation is likely to promote the degradation of significantly disordered proteins; however, the specific effect on the regulation of protein levels appears to be dependent on the mechanism of action of each stimulator due to the dynamic nature of the 20S CP. Our results reveal the potential of tailoring small molecule stimulators to influence the degradation of certain protein types and 20S CP substrates.
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spelling pubmed-83418742021-08-26 Protein degradation profile reveals dynamic nature of 20S proteasome small molecule stimulation Coleman, Rachel A. Mohallem, Rodrigo Aryal, Uma K. Trader, Darci J. RSC Chem Biol Chemistry Small molecules have been discovered to stimulate the 20S core particle (CP) of the proteasome to degrade proteins. However, the impact a 20S CP stimulator can have on the regulation of protein levels has not been fully characterized. Previous studies have focused on using one kind of stimulator to enhance the degradation of specific 20S CP substrates. We present here a study that utilizes several 20S CP stimulators to determine how each can affect the degradation of proteins in a biochemical assay with purified proteins and of an overexpressed GFP-fusion protein in cells. We also evaluate the effects of two stimulators on the whole cellular proteome in HEK-293T cells using label-free quantitative proteomic analysis for a broader understanding on their impact. Our studies demonstrate that 20S CP stimulation is likely to promote the degradation of significantly disordered proteins; however, the specific effect on the regulation of protein levels appears to be dependent on the mechanism of action of each stimulator due to the dynamic nature of the 20S CP. Our results reveal the potential of tailoring small molecule stimulators to influence the degradation of certain protein types and 20S CP substrates. RSC 2021-01-05 /pmc/articles/PMC8341874/ /pubmed/34458805 http://dx.doi.org/10.1039/d0cb00191k Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Coleman, Rachel A.
Mohallem, Rodrigo
Aryal, Uma K.
Trader, Darci J.
Protein degradation profile reveals dynamic nature of 20S proteasome small molecule stimulation
title Protein degradation profile reveals dynamic nature of 20S proteasome small molecule stimulation
title_full Protein degradation profile reveals dynamic nature of 20S proteasome small molecule stimulation
title_fullStr Protein degradation profile reveals dynamic nature of 20S proteasome small molecule stimulation
title_full_unstemmed Protein degradation profile reveals dynamic nature of 20S proteasome small molecule stimulation
title_short Protein degradation profile reveals dynamic nature of 20S proteasome small molecule stimulation
title_sort protein degradation profile reveals dynamic nature of 20s proteasome small molecule stimulation
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341874/
https://www.ncbi.nlm.nih.gov/pubmed/34458805
http://dx.doi.org/10.1039/d0cb00191k
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