Researchers from the University of Potsdam and the University of Cologne have unraveled the stepwise assembly of a central molecular machine responsible for protein degradation in cells – the eukaryotic proteasome. With the help of high-resolution cryo-electron microscopy, they were able to track the individual steps of their biogenesis. Their findings published today in “Nature Communications” challenge long-standing assumptions in the field and are important for research into aging processes and diseases, as well as for drug development.
Proteasomes are vital protein complexes that break down damaged or no longer needed proteins in cells. Using high-resolution cryo-electron microscopy (cryo-EM), the team led by Prof. Petra Wendler from the University of Potsdam and Prof. Jürgen Dohmen from the University of Cologne captured the structures of six early proteasome precursor complexes in yeast — including previously unknown intermediate states.
The new data show that the proteasome can assemble via two distinct routes, which differ in the order of the built-in beta subunits. Contrary to previous hypotheses, the assembly of this essential complex is not a rigid, linear process, but instead proceeds through multiple alternative pathways. “This was a surprise,” says Prof. Wendler. “An active proteasome is composed of 28 individual proteins. We were able to demonstrate that the activity-mediating subunits beta 1 and beta 5 can enter the complex independently of one another – a clear indication of flexibility in proteasome biogenesis which was not expected.”
The study also reveals how chaperone proteins guide the assembly process. The term chaperone refers to a specific type of proteins that support the maturation of other proteins, prevents unwanted interactions, and corrects errors. They play an important role in the development and aging of cells. This work shows that at the molecular level, a previously unknown chaperone segment keeps the central pore of the nascent proteasome open. This loop is only released after the final maturation step, ensuring that the complex is not activated prematurely.
„Proteasome assembly is a precisely choreographed process,” explains Prof. Jürgen Dohmen. „Our work demonstrates how structural changes in chaperones and proteasomal subunits are tightly coordinated to ensure that the complex is assembled correctly and only activated once all components are in place.”
These insights have broad implications for understanding cellular protein quality control, aging, and diseases such as cancer and neurodegenerative disorders. They also open new avenues for developing targeted therapies that modulate proteasome biogenesis.
According to the editorial board of “Nature Communications”, the paper is among the top 50 recent publications in the field of “Structural biology, biochemistry and biophysics” and was therefore distinguished as Editors’ Highlight . The work and investigations with the cryo-electron microscope were funded by the German Research Foundation (DFG).
Link to Publication: Eric Mark, Paula C. Ramos, Maria M. Nunes, Ana C. Matias, R. Jürgen Dohmen, Petra Wendler, 2026, Structural transitions in the stepwise assembly of proteasome core particles, Nature Communications, https://doi.org/10.1038/s41467-026-70525-w
Image: Assembly process of the proteasome in yeast cells. Proteasome precursors 13S-PC to 15S-PC and alternative pathways in which the b eta 1 subunit is added before beta 5 and beta 6, or beta 5 and beta 6 are incorporated first. Image: Petra Wendler
Contact:
Prof. Dr. Petra Wendler
Institute of Biochemistry and Biology
Tel.: +49 331 977-5130
E-Mail: petra.wendler@uni-potsdam.de
Media Information 24-03-2026 / Nr. 028
Nature Communications
Experimental study
Cells
Structural transitions in the stepwise assembly of proteasome core particles
24-Mar-2026