Advanced microscopes help scientists understand how cells break down proteins


Researchers at the University of Chicago, in the United States, have used advanced electron microscopes to delve into the process of protein degradation, as published in the journal ‘Nature’.

And from there they have described the structure of a key enzyme that helps mediate ubiquitination in yeast, part of a cellular process called the N-degradation pathway that may be responsible for determining the degradation rate of up to 80% of the equivalent proteins in humans.

Proteins are the building blocks of all living things. Much research is being done on how these proteins are made and what they do, from the enzymes that carry out chemical reactions to the messengers that transmit signals between cells. In 2004, Aaron Ciechanover, Avram Hershko, and Irwin Rose won the Nobel Prize in Chemistry for a different but just as important process in the protein machinery: how organisms break down proteins when they have finished doing their jobs.

Protein degradation is a carefully orchestrated process. Proteins are marked for elimination with a molecular tag called ubiquitin, and then fed into proteasomes, a kind of cellular paper shredder that breaks proteins into small pieces. This process of ubiquitination, or labeling of proteins with ubiquitin, is involved in a wide range of cellular processes, including cell division, DNA repair, and immune responses.

Failures in this pathway can lead to the accumulation of damaged or misfolded proteins, which underlies the aging process, neurodegeneration and some rare autosomal recessive disorders, so understanding it better offers the opportunity to develop treatments.

Dr. Minglei Zhao, associate professor of Biochemistry and Molecular Biology, and his colleagues studied an E3 ligase – a type of enzyme that helps bind larger molecules together – called Ubr1. In bread yeast, Ubr1 helps start the ubiquitination process by binding ubiquitin to proteins and lengthening it into a chain of molecules known as a polymer.

Polymers, which are more commonly known as the building blocks of synthetic materials like plastics, also occur naturally when large molecules (in this case ubiquitin) are connected into repeating subunits.

“Until this study, we didn’t know much about how ubiquitin polymers are structurally formed,” says Zhao. “Now we are starting to get an idea of ​​how it installs first in the protein substrate, and then how the polymers are formed specifically. This is a milestone in understanding polyubiquitination at an almost atomic level, “he says.

In this study, Zhao and his team used some chemical biology techniques to mimic the initial steps in the process of binding ubiquitin to proteins. They then employed another Nobel Prize-winning innovation called electron cryomicrography (cryo-EM) to capture the process.

Cryo-MS consists of freezing protein solutions and using a powerful electron microscope to image individual molecules or subcellular structures. About 10 years ago, advances in hardware and software produced microscopes and detectors that could capture molecular images with much higher resolution.

In 2017, Jacques Dubochet, Joachim Frank, and Richard Henderson won the Nobel Prize in Chemistry for developing cryo-EM techniques, which allow researchers to create a snapshot that literally freezes the “live” action of a biological process.

Zhao’s team leveraged a $ 10 million investment from the Division of Biological Sciences in the Advanced Electron Microscopy Facility to use cryo-EM to study ubiquitination in more detail. They were able to describe the structure of several intermediate enzyme complexes involved in the pathway, which will help researchers looking for ways to target proteins with drugs or intervene in a malfunctioning protein breakdown process.

“Cryoelectronics is exciting because once the data is processed, a new structure appears that has never been seen before,” says Zhao. “Now we can use what we have learned and reuse the enzymes by introducing small molecules or mixtures of peptides to degrade. the proteins we want. “

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Advanced microscopes help scientists understand how cells break down proteins