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Related Concept Videos

The Proteasome01:13

The Proteasome

1.9K
Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
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The Proteasome02:18

The Proteasome

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Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
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The Proteasome02:18

The Proteasome

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The Proteasome Structure01:17

The Proteasome Structure

2.0K
The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
2.0K
Regulated Protein Degradation02:58

Regulated Protein Degradation

9.1K
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
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Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

13.6K
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
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Related Experiment Video

Updated: Mar 1, 2026

Examining Proteasome Assembly with Recombinant Archaeal Proteasomes and Nondenaturing PAGE: The Case for a Combined Approach
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Proteasome Activation by Small Molecules.

Yves Leestemaker1, Annemieke de Jong2, Katharina F Witting1

  • 1Division of Cell Biology II, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Department of Chemical Immunology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.

Cell Chemical Biology
|May 30, 2017
PubMed
Summary
This summary is machine-generated.

Boosting 26S proteasome activity shows therapeutic potential for neurodegenerative diseases. Inhibiting p38 MAPK enhances proteasome function, reducing toxic alpha-synuclein and improving cell survival.

Keywords:
activity-based protein profilingproteasome activatorubiquitin-proteasome systemα-synuclein

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Area of Science:

  • Biochemistry
  • Neuroscience
  • Pharmacology

Background:

  • The 26S proteasome is crucial for protein homeostasis.
  • Dysfunctional protein degradation is implicated in neurodegenerative diseases.
  • Targeting proteasome activity offers a therapeutic strategy.

Purpose of the Study:

  • To identify compounds that enhance 26S proteasome activity.
  • To investigate the role of p38 MAPK in proteasome regulation.
  • To assess the therapeutic potential of proteasome activators in neurodegeneration models.

Main Methods:

  • High-throughput chemical genetics screen using a proteasome activity probe.
  • Live-cell fluorescence-activated cell sorting (FACS) assay.
  • Genetic and chemical inhibition of p38 MAPK pathway components (ASK1, MKK6, MK2).

Main Results:

  • Over ten compounds identified that increase proteasome activity.
  • PD169316, a p38 MAPK inhibitor, demonstrated potent proteasome activation.
  • Inhibition of the p38 MAPK pathway enhanced proteasome activity.
  • Proteasome activation reduced alpha-synuclein levels and improved cell survival in models of neurodegeneration.

Conclusions:

  • Activation of 26S proteasome activity is a viable therapeutic approach for neurodegenerative diseases.
  • The p38 MAPK pathway is a key regulator of proteasome function.
  • Distinct molecular mechanisms can be employed to activate the proteasome for therapeutic benefit.