CHIP Ubiquitin Ligase Molecular Switch May Help in Proper Body and Cell Function Controlling Life Expectancy

University of Cologne researchers have recently shown that CHIP may also identify itself with ubiquitin, preventing the formation of its dimer. The research was conducted by the University of Cologne's Cluster of Excellence for Cellular Stress Responses in Aging-Associated Diseases (CECAD), and it was recently published in the journal Molecular Cell.

What is Ubiquitylation?

According to Avacta, ubiquitylation, also known as ubiquitination, is the act of binding the tiny protein ubiquitin to a specific protein in eukaryotic organisms. Ubiquitin is present in almost all of the organisms' tissues. Although the most frequent link scientists make with this process is that it designates proteins for breakdown, ubiquitylation might affect a protein's activity or alter its function inside the cell. According to the notion, ubiquitylation enables cells to keep track of a molecule's usage, increasing the likelihood that the molecule will be broken down when it has been present for a while.

A ubiquitin ligase (E3) and a ubiquitin-conjugating enzyme (E2) work together to attach ubiquitin to the lysine groups of target proteins. These proteins make it easier for ubiquitin to be activated and transferred to the target protein or to other ubiquitin proteins that are already bound to the target protein.

What is CHIP?

Researchers identified CHIP as a ubiquitin ligase involved in the degradation of misfolded proteins in a study published in Molecular Cell in 2005.

In the Embo Reports, the researchers stated that CHIP demonstrated activity for self-ubiquitylation separate from target ubiquitylation. It includes their findings suggesting that CHIP can be seen as a quality-control E3 that works with molecular chaperones to specifically ubiquitylate unfolded proteins.

CHIP Monomer vs CHIP Dimer

Through tests involving human cells and the nematode Caenorhabditis elegans, the scientists were able to conclude that the CHIP monomer more efficiently controls insulin signaling compared to the CHIP dimer. According to current research, the insulin receptor can be controlled more efficiently when the protein CHIP is acting alone as opposed to when it is in a paired form. CHIP frequently manifests as a homodimer, which is an association of two identical proteins.

According to the study's first author, Vishnu Balaji, the condition of the cell determines whether CHIP functions alone or in pairs. Under stress, too many misfolded proteins as well as the assistance proteins that bind to CHIP are present. It inhibits the self-ubiquitin labeling process known as auto-ubiquitylation. CHIP can also designate the helper proteins for destruction after successfully removing the damaged proteins. As a result, CHIP can ubiquitylate itself and resume acting as a monomer.

Proper Cell Function

It is crucial to get rid of damaged proteins in order to maintain proper cell function. Thorsten Hoppe said that the monomeric and dimeric states of CHIP must be in equilibrium for the body to function properly. Hoppe said that it is intriguing that neurodegenerative diseases appear to disturb the monomer-dimer balance of CHIP. For instance, CHIP is altered at many locations and primarily performs as a dimer in spinocerebellar ataxias. A change to more monomers in this situation might be therapeutic.

The next step is for the researchers to determine if there are any further proteins or receptors that the CHIP monomer interacts with and controls their function. In order to create more specialized treatments in the future, researchers are particularly curious about which tissues, organs, and diseases have higher concentrations of CHIP monomers or dimers.

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