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Study provides new insights into the processes involved in the assembly of the proteasome, a key component of cellular protein quality control that plays a significant role in ageing and diseases such as cancer and neurodegenerative disorders.The article appeared in Nature Communications and has been selected as an Editors’ Highlight.
A new study conducted by researchers from the University of Potsdam and the University of Cologne has deciphered the step-by-step assembly of the eukaryotic proteasome. Eukaryotes are organisms whose cells have a clearly defined nucleus and different compartments within the cell. The proteasome is one of the key molecular machines responsible for the degradation of proteins that are defective or no longer needed within cells. The central protease chamber of the proteasome consists of two identical halves, each composed of two rings comprising seven alpha or seven beta subunits. The two inner beta rings form a chamber in which defective proteins are broken down. The study’s results, published in Nature Communications under the title “Structural transitions in the stepwise assembly of proteasome core particles”, show that the assembly of this vital complex does not follow a rigid, linear pattern, but rather utilizes several alternative pathways – a discovery that challenges established views in research. The article was honoured as an Editors' Highlight.
The findings have far-reaching implications for understanding cellular protein quality control, ageing and diseases such as cancer or neurodegenerative disorders, in which proteasome dysfunction plays a role. They also open up new avenues for the development of targeted drugs that influence proteasome biogenesis. The research was funded by the German Research Foundation (DFG).
Using high-resolution cryo-electron microscopy (cryo-EM), a team led by Professor Dr Petra Wendler of the University of Potsdam and Professor Dr Jürgen Dohmen of the University of Cologne has characterized the structures of six early proteasome precursor complexes (13S-PC to 15S-PC) in yeast – including previously unknown intermediate stages. The data show that the proteasome can be assembled via two different pathways, which differ in the order in which the beta subunits are incorporated into the rings of the proteasome: One pathway in which the Beta1 subunit is incorporated first, followed by Beta5 and Beta6, and another in which Beta5 and Beta6 are incorporated first.
“That was a surprise,” says Petra Wendler. “Beta1 can enter the complex independently of Beta5 and Beta6 – an indication of a flexibility in proteasome biogenesis that we hadn’t expected.”
The study also reveals how the assembly helper proteins Ump1 and Pba1-Pba2 – so-called chaperones – control the assembly process. A previously unknown region of the Pba1 protein inserts between two alpha subunits and acts like a molecular wedge, keeping the central pore of the maturing proteasome open. It is only released after the final stage of maturation, ensuring that the complex is only activated once it is fully assembled. Pba1-Pba2 is then recycled, whilst Ump1 is degraded by the mature proteasome.
The results also show that the catalytic centres of the proteasome, where proteins are broken down after assembly, are only correctly structured – and thus activated – once the two halves (15S-PC) have joined together. This is mediated by the entry of the last of the seven beta subunits (Beta7). This mechanism prevents premature activation of the proteasome before the chamber is closed.
“The assembly of the proteasome is a precisely choreographed process,” says Jürgen Dohmen. “Our work demonstrates how structural changes in chaperones and proteasome subunits are precisely coordinated to ensure correct assembly of the proteasome and activation only once all components have taken up their correct positions.”
Professor Dr R. Jürgen Dohmen
Institute for Genetics, University of Cologne
+49 221 470 4862
j.dohmen@uni-koeln.de
Professor Dr Petra Wendler
Institute of Biochemistry and Biology
University of Potsdam
+49 331 9775130
petra.wendler@uni-potsdam.de
DOI: 10.1038/s41467-026-70525-w
https://www.nature.com/ncomms/editorshighlights
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