Flexibly Assembled: Latest Insights into Proteasome Biogenesis
A new study by researchers at the University of Potsdam and the University of Cologne has revealed a more nuanced understanding of how eukaryotic proteasomes are assembled, challenging previous linear models. The research, published in Nature Communications and highlighted by the editors, has implications for understanding aging, cancer, and neurodegenerative diseases.
The Proteasome: A Cellular Recycling Center
The proteasome is a critical molecular machine responsible for breaking down damaged or unnecessary proteins within cells. Its central protease chamber consists of two identical halves, each composed of rings of alpha and beta subunits. The inner beta rings form a chamber where proteins are degraded. Proper proteasome function is essential for maintaining cellular health and responding to stress.
Alternative Assembly Pathways
Traditionally, proteasome assembly was thought to follow a rigid, step-by-step process. However, the new study demonstrates that the proteasome can be assembled via at least two distinct pathways. Using high-resolution cryo-electron microscopy (cryo-EM), the researchers examined structures of early proteasome precursors in yeast, identifying previously unknown intermediates. These pathways differ in the order in which beta subunits are incorporated into the proteasome rings: one pathway incorporates the beta1 subunit first, followed by beta5 and beta6, while the other incorporates beta5 and beta6 first.1
“Beta1 can enter the complex independently of Beta5 and Beta6 – indicating a flexibility in proteasome biogenesis that we did not expect,” said Petra Wendler, Professor at the University of Potsdam.3
Chaperone Proteins and Assembly Control
The assembly process is carefully controlled by chaperone proteins, specifically Ump1 and Pba1-Pba2. The study revealed a previously unknown function of the Pba1 protein. A section of Pba1 slides between alpha subunits, acting as a “molecular wedge” that keeps the proteasome’s central pore open during maturation. This wedge is released only when the proteasome is fully assembled, preventing premature activation. Pba1-Pba2 is then recycled, while Ump1 is degraded by the mature proteasome.1
Preventing Premature Activation
The catalytic centers within the proteasome, responsible for protein degradation, are only correctly structured and activated after the two halves of the proteasome connect. This connection is mediated by the incorporation of the final beta subunit (Beta7). This mechanism ensures the proteasome remains inactive until fully assembled, preventing unintended protein breakdown.1
Implications for Disease and Drug Development
“The assembly of the proteasome is a precisely choreographed event,” said Jürgen Dohmen, Professor at the University of Cologne. “Our operate shows how structural changes in chaperones and proteasomal subunits are precisely coordinated to ensure that the proteasome is assembled correctly and only activated when all components are in their correct places.”3
These findings have significant implications for understanding cellular protein quality control, the aging process, and diseases where proteasome dysfunction plays a role, such as cancer and neurodegenerative disorders. The research as well opens avenues for developing targeted drugs that can influence proteasome biogenesis.3
Funding: This research was funded by the German Research Foundation (DFG).3
Contact
Professor Dr. R. Jürgen Dohmen
Institute of Genetics at the University of Cologne
+49 221 470 4862
j.dohmen@uni-koeln.de
Original Publication
DOI: 10.1038/s41467-026-70525-w