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Cell treatment rounds and removes damaged proteins



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In a new paper with results that senior author Eric Strieter at the University of Massachusetts Amherst calls “supremely surprising”, he and his team of chemistry labs report that they have found a way. An enzyme called UCH37 regulates the cell̵

7;s waste management system.


“It took us eight years to find it, and I’m very proud of this work. We had to develop a lot of new methods and tools to understand what this enzyme is doing,” Strieter said.

As he explains, a very large protease called a proteasome is responsible for the majority of proteins in the cell; It can be made up of 40 proteins. For over 20 years, he added, UCH37 was one of the regulating enzymes bound to the proteasome, “but no one understood what it was doing.”

The key to the whole process, he adds, is how complex changes in a small protein called ubiquitin can be. “In addition to modifying other proteins, ubiquitin self-regulates leading to a series of chains. Some of these chains can have wide branching. We found that UCH37 removes branching points from the chain, allowing for the process to undergo branching. Degradation takes place. “

Write this week in Molecular cells, he and the first author and doctor. Candidate Kirandeep Deol, who leads and conducts experiments, and co-authors Sean Crowe, Jiale Du, Heather Bisbee, and Robert Guenette, discuss how they respond to questions. The work was supported by the National Institute of General Medical Science of the NIH.

This progress could eventually lead to a new cancer treatment, Strieter said, because cancer cells need proteasomes to grow and multiply. “Many cancer cells are essentially addicted to proteasome function,” he points out. “Its cells produce protein at such a rapid rate that it makes a mistake and if they are not removed, the cell cannot function. Since UCH37 aids in protein removal, it could be a target. Useful therapies for adding proteasome inhibitors have been successful in the clinic. “

To begin their multi-year process, Strieter said, “we had to devise a way to create multiple ubiquitin chains representing potential diversity in a cell. Using the new ubiquitin chain library. that allows us to interrogate UCH37 activity in a controlled environment. That series of experiments gave us the first clue that this enzyme is doing something unique. “

Another new method they developed uses mass spectrometry to describe the architecture of ubiquitin chains in complex mixtures. “This allowed us to see that the activity we found with our substrate library also occurred in a heterogeneous mixture,” Strieter said. Finally, the chemists used the CRISPR gene-editing tool to remove UCH37 from cells to measure the effect of UCH37 on proteasome-mediated degradation in vitro and intracellularly.

This technique leads to another surprise. “Instead of acting as expected and fighting degeneration, it turns out that UCH37 removed branch points from the ubiquitin chain to help break down proteins,” Strieter said. He added: “You would think that by eliminating the degradation signal the degradation would be attenuated, but it doesn’t work that way.

In future experiments, Strieter and colleagues hope to further explore the degradation process and explore in more detail how UCH37 manages to regulate cell function.


Proteasome phase cleavage for destruction


More information:
Kirandeep K. Deol et al, Proteasome-Bound UCH37 / UCHL5 Ubiquitin chains to promote degeneration, Molecular cells (Year 2020). DOI: 10.1016 / j.molcel.2020.10.017

Provided by University of Massachusetts Amherst

Quote: How cell processes round up and remove damaged proteins (2020, November 7) retrieved November 7, 2020 from https://phys.org/news/2020-11-cell -dump-proteins.html

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