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Related Concept Videos

Regulated Protein Degradation02:58

Regulated Protein Degradation

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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.
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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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Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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The Unfolded Protein Response01:37

The Unfolded Protein Response

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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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Directing Proteins to the Rough Endoplasmic Reticulum01:34

Directing Proteins to the Rough Endoplasmic Reticulum

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The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
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Post-translational Translocation of Proteins to the RER01:27

Post-translational Translocation of Proteins to the RER

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A sizable fraction of proteins destined for ER are first synthesized in the cell cytosol and then transported across the ER membrane–a process called post-translational translocation. Similar to cotranslationally translocated proteins, these proteins also use the Sec translocon complex to enter the ER lumen.
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
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High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
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Targeted Protein Degradation through E2 Recruitment.

Nafsika Forte1,2,3, Dustin Dovala2,4, Matthew J Hesse2,4

  • 1Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States.

ACS Chemical Biology
|March 20, 2023
PubMed
Summary
This summary is machine-generated.

This study introduces a new method for targeted protein degradation (TPD) by recruiting E2 ubiquitin conjugating enzymes. This approach enables the degradation of specific proteins like BRD4 and the androgen receptor.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeted protein degradation (TPD) utilizes proteolysis targeting chimeras (PROTACs) to degrade specific proteins.
  • PROTACs typically recruit E3 ubiquitin ligases, but this study explores recruiting other components of the ubiquitin-proteasome system (UPS).

Purpose of the Study:

  • To discover novel recruiters for core ubiquitin-proteasome system (UPS) components beyond E3 ligases.
  • To develop heterobifunctional degraders that leverage E2 ubiquitin conjugating enzymes for targeted protein degradation.

Main Methods:

  • Covalent chemoproteomic approaches were employed to identify a covalent recruiter for the E2 ubiquitin conjugating enzyme UBE2D.
  • The recruiter, EN67, was designed to target an allosteric cysteine (C111) on UBE2D without inhibiting its enzymatic activity.

Main Results:

  • A novel covalent recruiter (EN67) for UBE2D was discovered.
  • Heterobifunctional degraders incorporating the UBE2D recruiter successfully degraded neo-substrate targets, including BRD4 and the androgen receptor, in a UBE2D-dependent manner.

Conclusions:

  • Recruiting core UPS machinery, specifically E2 ubiquitin conjugating enzymes, is a viable strategy for TPD.
  • Covalent chemoproteomics is effective for discovering novel recruiters for UPS components, expanding TPD capabilities.