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Regulated Protein Degradation

Regulated Protein Degradation

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...

Regulated Protein Degradation

Regulated Protein Degradation

The Proteasome

The Proteasome

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...

The Proteasome

The Proteasome

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...

The Proteasome

The Proteasome

The Proteasome Structure

The Proteasome Structure

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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Targeted Protein Degradation by Small Molecules.

Daniel P Bondeson¹, Craig M Crews¹

¹Department of Molecular, Cellular, and Developmental Biology, Department of Chemistry, and Department of Pharmacology, Yale University, New Haven, Connecticut 06511;

Annual Review of Pharmacology and Toxicology

|October 13, 2016

Summary

Researchers are reviewing new ways to use small molecules to selectively degrade disease-causing proteins. These innovative techniques repurpose cellular protein homeostasis networks for therapeutic benefit and research.

Keywords:

IMiDs PROTACs chemical knockdown protein degradation ubiquitin proteasome system

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Cycloheximide Chase Analysis of Protein Degradation in Saccharomyces cerevisiae

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Area of Science:

Biochemistry
Molecular Biology
Pharmacology

Background:

Cellular health relies on tightly regulated protein homeostasis networks.
Existing therapeutics often disrupt these networks.
New methods repurpose these networks to degrade disease-related proteins.

Purpose of the Study:

To review recent advances in selective protein degradation using small molecules.
To highlight techniques with direct clinical applications.
To describe methods suitable for the broader biomedical research community.

Main Methods:

Review of literature on small-molecule-induced protein degradation.
Categorization of techniques based on clinical applicability and synthetic chemistry requirements.
Analysis of current and potential therapeutic applications.

Main Results:

Identification of all-small-molecule techniques with direct clinical relevance.
Description of emerging techniques requiring minimal synthetic chemistry.
Demonstration of small molecules as tools to control intracellular protein levels.

Conclusions:

Selective protein degradation using small molecules offers novel therapeutic potential.
These approaches can target previously undruggable proteins.
New techniques provide innovative tools for biomedical research and drug discovery.