Researchers from Scripps Research have discovered how the proteasome, which is made of protein complexes in the cell that breaks down damaged and unwanted proteins, converts energy into motion to unfold target proteins for recycling.

What is the proteasome?

The proteasome is a protein complex whose job is to break down and recycle proteins that have become damaged or are no longer required. It achieves this via a process called proteolysis, a chemical reaction that breaks the peptide bonds, thus allowing the target protein to be destroyed and broken down into its constituent parts, which become ready to be reused to make new proteins. The enzymes that facilitate this recycling process are known as proteases.

During the aging process, increasing numbers of misfolded proteins accumulate. They impair cell function, cause aberrant behavior, and disrupt tissue homeostasis; this failure of proteostasis (the creation of correctly folded proteins) is proposed to be one of the reasons we age. The proteasome is a critical component in the proteostasis network, and understanding how it works is important in understanding aging and could have implications for diseases such as Alzheimer’s and Parkinson’s, which are thought to be caused by the accumulation of misfolded proteins.

The 26S proteasome is the primary eukaryotic degradation machine and thus critically involved in numerous cellular processes. The hetero-hexameric ATPase motor of the proteasome unfolds and translocates targeted protein substrates into the open gate of a proteolytic core, while a proteasomal deubiquitinase concomitantly removes substrate-attached ubiquitin chains. However, the mechanisms by which ATP hydrolysis drives the conformational changes responsible for these processes have remained elusive. Here we present the cryo-EM structures of four distinct conformational states of the actively ATP-hydrolyzing, substrate-engaged 26S proteasome. These structures reveal how mechanical substrate translocation accelerates deubiquitination, and how ATP-binding, hydrolysis, and phosphate-release events are coordinated within the AAA+ motor to induce conformational changes and propel the substrate through the central pore.

The secrets of the proteasome revealed

The researchers of this new study, which was published in the popular journal Science, have spent the last five years or more examining the intimate details of the proteasome [1]. Revealing the mysteries of the proteasome has been challenging due to its highly complex structure, which contains a “motor” and a myriad of moving bits and pieces.

Using cryo-electron microscopy (cryo-EM), the team was able to visualize the internal structure and workings of the proteasome. Cryo-EM is a new technology that allows researchers to freeze biological complexes in place partway through their movements, thus allowing the team to explore complex biological processes using images taken at different points in time. The technique was developed by Jacques Dubochet, Joachim Frank, and Richard Henderson, and it won the 2017 Nobel Prize for Chemistry.

The researchers used cryo-EM to take snapshots of the proteasome at work, which allowed them to fully understand how the “motor” driving the process works and interacts with the moving parts. They were able to see exactly how the proteasome works during protein degradation at a level of detail never seen before.

Perhaps most importantly, the researchers discovered how ATP, the universal energy currency of cells, powers the proteasome’s motor, allowing it to drag target proteins into its central channel to be processed and broken down. They could see clearly how it pulls proteins through its channel and then positions and unfolds them, getting them ready to be fed as a single strand into its degradation chamber.


These researchers have advanced our understanding of aging and how the proteasome works. This research has implications for understanding how diseases such as Alzheimer’s and Parkinson’s happen and how we might deal with increasing amounts of misfolded proteins caused by the failure of the proteasome. If we can understand why the proteasome fails when faced with the misfolded proteins associated with these neurogenerative diseases, we will be better placed to develop therapies to remove them.


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[1] Andres, H., Goodall, E. A., Gates, S. N., Lander, G. C., & Martin, A. (2018). Substrate-engaged 26S proteasome structures reveal mechanisms for ATP-hydrolysis–driven translocation. Science, 362(6418), eaav0725.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
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