Scientists use advanced microscopes to dig deeper into the process of degrading proteins

Proteins are the building blocks of all living things. There is a lot of research taking place on how proteins are made and what they do in the process, from enzymes that perform chemical reactions to messengers that send signals between cells. In 2004, Aaron Ciechanover, Avram Hershko and Irwin Rose won the Nobel Prize in Chemistry for another, but equally important process of protein machinery that explains how organisms break down proteins when they have completed their job.

Protein degradation is a meticulously planned process that is meticulously planned. Proteins are marked for disposal with a molecular label , known as ubiquitin, and then is fed into proteasomes, which is a type of cellular shredder that breaks up proteins into smaller pieces. The process of Ubiquitination (or the labeling of proteins using Ubiquitin) is involved in many cellular processes including cell division, DNA repair, and immune responses.

In a study that was published in Nature on November 17, 2021, researchers from the University of Chicago used advanced electron microscopes to delve deeper into the process of protein degradation. The structure of the key enzyme that mediates ubiquitination in yeast was described by researchers from the University of Chicago. This enzyme is a part of the N-degron pathways, which may be the cause of the rate at which equivalent proteins in humans are destroyed. In the N-degron pathway, malfunctions can lead to accumulation of damaged or misfolded protein, which underlies the aging process, neurodegeneration, and some rare autosomal recessive diseases, which is why understanding it better gives the possibility of developing treatments.

Minglei Zhao, PhD, Assistant Professor of Biochemistry and Molecular Biology, and his colleagues have studied an E3 ligase-;a type of enzyme that helps join larger molecules together. It is known as Ubr1. Ubr1 is an enzyme that binds ubiquitin proteins to proteins. It then extends the chain to form the compound that is known as polymers. Polymers, also considered to be the basic building blocks of synthetic materials like plastics, are also naturally created when large molecules (in this case, ubiquitin) are joined in repeating units.

We had no idea about the structure formation of ubiquitin polymers prior this study. We’re beginning to gain an understanding of how they are first positioned on the protein substrate, and then how the polymers are formed in a specific way for linkage. This is a significant step in the understanding of the process of polyubiquitination at an the atomic level.”

Minglei Zhao, PhD, Assistant Professor of Biochemistry and Molecular Biology

Zhao and his team used chemical biology techniques to reproduce the initial steps involved in attaching ubiquitin proteins to proteins in this study. To capture the process, they used cryo-electron microscopic (cryoEM) which is a Nobel Prize-winning invention. Cryo-EM uses flash-freezing proteins to create images. Then, electron microscopes are used to capture images of subcellular and individual molecules. structures. Around 10 years ago, breakthroughs in hardware and software led to the development of microscopes and detectors that were able to capture molecular images with a higher resolution. In 2017, Jacques Dubochet, Joachim Frank and Richard Henderson won the Nobel Prize in Chemistry for developing cryo-EM techniquesthat allow researchers to create snapshots that literally freezes “live” action of a biological process.

Zhao’s team used a $10 million investment from the Biological Sciences Division at the Advanced Electron Microscope Facility to make use of cryoEM to study ubiquitination closely. They were able describe the structure of several intermediate enzyme complexes that are involved in the process, which will help researchers looking for ways to target proteins with drugs or to intervene in a malfunctioning protein degradation process.

“Cryo-EM is exciting because after the data processing is done, a new structure pops out that you’ve never before seen,” Zhao said. “Now we can utilize what we know and reuse enzymes by introducing small molecules, or a combination of peptides to degrade the proteins we desire.”

Journal reference:

Pan, M., and al. (2021). Structural insights into Ubr1’s N-degron polyubiquitination. Nature.

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Gemma Wilson

Gemma is a journalism graduate with keen interest in covering business news – specifically startups. She has as a keen eye for technologies and has predicted quite a few successful startups over the last couple of years.

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