Issue 2, 2021

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

Abstract

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.

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

Supplementary files

Article information

Article type
Paper
Submitted
21 Okt. 2020
Accepted
21 Dec. 2020
First published
05 Janv. 2021
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2021,2, 636-644

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

R. A. Coleman, R. Mohallem, U. K. Aryal and D. J. Trader, RSC Chem. Biol., 2021, 2, 636 DOI: 10.1039/D0CB00191K

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