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Related Concept Videos

The Proteasome01:13

The Proteasome

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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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Proteomics01:33

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A proteome is the entire set of proteins that a cell type produces. We can study proteomes using the knowledge of genomes because genes code for mRNAs, and the mRNAs encode proteins. Although mRNA analysis is a step in the right direction, not all mRNAs are translated into proteins.
Proteomics is the study of proteomes' function. It involves the large-scale systematic study of the proteome to denote the protein complement expressed by a genome. Scientist Mark Wilkins coined the term...
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The Proteasome Structure01:17

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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...
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Proteomic approaches advancing targeted protein degradation.

Gajanan Sathe1, Gopal P Sapkota1

  • 1MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

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|October 1, 2023
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Summary

Targeted protein degradation (TPD) utilizes cellular pathways to eliminate disease-causing proteins. This review highlights proteomic methods advancing TPD therapeutics, focusing on degrader development and mechanism of action insights.

Keywords:
PROTACchemoproteomicsmolecular glueproteomicstargeted protein degradation

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Targeted protein degradation (TPD) is a rapidly advancing therapeutic modality.
  • Current TPD approaches, including proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs), leverage cellular ubiquitin-dependent proteolytic pathways.
  • Despite clinical progress, challenges remain in developing effective, selective, and tissue-penetrant degraders and fully understanding their mechanisms.

Purpose of the Study:

  • To review recent progress in addressing challenges in targeted protein degradation.
  • To highlight the application of proteomic approaches in TPD research and development.
  • To provide insights into degrader development, including target engagement, selectivity, efficacy, safety, and mode of action.

Main Methods:

  • Review of current literature on targeted protein degradation.
  • Discussion of proteomic techniques and their utility in TPD.
  • Analysis of advancements in understanding degrader mechanisms.

Main Results:

  • Proteomic approaches are crucial tools for understanding TPD.
  • These methods provide insights into target engagement, degradation selectivity, efficacy, and safety.
  • Progress has been made in overcoming challenges related to degrader development.

Conclusions:

  • Targeted protein degradation holds significant therapeutic potential.
  • Proteomic strategies are indispensable for advancing TPD research and drug development.
  • Continued innovation in understanding degrader mechanisms will accelerate clinical translation.