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Cells organize their molecules in distinct functional areas. While textbooks usually refer to membrane-bound organelles such as mitochondria and cell nuclei, recent studies have also revealed organelles without membranes. These include stress granules and proteasome storage granules (PSGs). In the past, these membraneless organelles were only visible as “droplets” using a fluorescence microscope. Now, researchers from the Max Planck Institute of Biochemistry in Martinsried, University Medical Center Göttingen, and University of Toronto have defined the detailed structures of molecules in PSGs for the first time, using cryoelectron tomography. The results were published in the journal Cell.
Key points
- The arrangement of molecules inside membraneless organelles such as proteasome storage granules (PSGs) was previously unknown
- Under conditions of nutrient deficiency, proteasomes inside yeast cells cluster to form PSGs
- Cryoelectron microscopy images show that PSGs contain fully-assembled proteasomes maintained in an inactive state in a paracrystalline – partly crystalline but without long-range order – arrangement
- This finding expands understanding of membraneless organelles to those beyond liquid-like droplets that, like PSGs, have specifically arranged building blocks
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A proteasome is a large protein complex that works as an energy powered “protein shredder,” eliminating specific unneeded or damaged proteins by chopping them into small pieces. Proteasomes are found in all eukaryotes, from yeast to humans, and are essential for life. Proteasomes are also essential for tumor cells to respond to some anti-cancer drugs. When certain nutrients or other sources of cellular energy are too low, the locations of proteasomes inside cells are visibly altered. As key executioners of cellular well-being and functions, proteasomes are a critical focus of research.
Professor Brenda Schulman, Director at the Max Planck Institute (MPI) of Biochemistry, explains: "Thanks to the great collaboration with the pioneer in the field of cryoelectron tomography, Professor Wolfgang Baumeister, we are now able to understand how proteasome storage granules function at the molecular level. We knew that many molecular machines assemble into membrane-less organelles, but to truly understand their function, we needed to see their molecular structure.”
Paracrystalline structure of proteasome storage granules
Dr. Cordula Enenkel, an expert in PSG research who works with structural biologist Prof. Oliver Ernst at the University of Toronto, explains: “We subjected yeast cells to energy stress by depriving them of glucose or blocking mitochondrial ATP production. This created ATP — the cells' energy source — scarcity. In response, the cells shut down their energy-intensive proteasomes by arranging them into PSGs.” Ernst adds, “We recognized that visualizing the structures of proteasome storage granules would be crucial to understanding this fascinating cellular strategy to cope with metabolic stress, but this was not possible with purified proteasomes.”
Dr. Xiaomeng Tang, one of the first authors of the study from the MPI of Biochemistry and the University Medical Center Göttingen (UMG), explains: We studied the proteasome storage granules in their natural environment — inside cells. Cryo-electron tomography (ET) enabled us to view the PSGs with a resolution of 0.9 nanometers, revealing structural details that were previously impossible to see. We saw for the first time that individual proteasomes become arranged into precise, repetitive structures like crystals. This was very informative, because what we saw contradicted expectations that PSGs would assemble into amorphous clusters or dynamic liquid droplets."
The team deciphered the detailed assembly of the PSGs. “The proteasomes first form trimers. This means that three proteasomes bind together. This has never been observed in cells before,” Tang continues. “These trimers then stack up to form fibers. The fibers bind together to form bundles.”
Cryo-electron tomography as a key technology
Co-first author Dr. Lu Qu from the MPI of Biochemistry and the UMG explains: “We were only able to demonstrate this proteasome arrangement within cells, but not in test tubes. When we tried to isolate the PSGs, the structures disintegrated – that’s why cryoelectron tomography was essential.”
In yeast cells, the PSGs remain fully assembled but inactive so they do not burn energy during energy shortage. Qu adds, “The proteasomes are kept in an inactive state by specific protein-protein interactions. The resulting paracrystalline assembly is stable, but it can also be shattered. This allows rapid reactivation of the fully-assembled proteasomes as soon as a source of energy becomes available. When the researchers supplied glucose to the starved cells, the proteasomes returned to their normal functioning structures within an hour.”
A paradigm shift: A membraneless organelle where structure determines function
Brenda Schulman explains: "The discovery provides a new view of membraneless organelle formation, through contacts between well-structured regions of molecular machines. This allows PSGs to safely store proteasomes – which are energetically-costly to make, and essential – in reserve, ready for deployment when cellular conditions improve.” Prof. Baumeister sums it up: “Studying structures inside of cells – like proteasomes in their native environment – fundamentally changes our understanding of cellular organization and function."
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Glossary
ATP: Abbreviation for adenosine triphosphate; the universal energy source for all cells, providing chemical energy. It consists of a mononucleotide bound to energy-rich phosphate residues. When needed, ATP is converted to ADP by splitting off a phosphate group, releasing energy.
Paracrystalline: a molecular arrangement with repeating structural units that form organized patterns locally, but lacks the perfect regularity extending throughout the entire structure that defines crystals.
Proteasome: is a cylindrical protein complex in eukaryotic cells that acts as a cellular “protein shredder.” Proteins that are marked with ubiquitin, damaged, or superfluous are directed into the proteasome, where they are broken down into small peptides. Proteasome function consumes ATP.
Proteasome storage granules: short PSG; are specialized structures in the cell that temporarily store proteasomes (the “protein shredders”) during conditions when ATP is scarce.
Protein degradation: is the process by which cells break down proteins into smaller peptides and amino acids to maintain protein balance and regulate cell functions.
Stress granules: are membraneless organelles containing specific proteins and RNAs, which form during certain stresses to temporarily reduce protein production and thus protect the cell until conditions improve.
Prof. Brenda Schulman, Ph.D.
Dpt. of Molecular Machines and Signaling
Max Planck Institute of Biochemistry
Am Klopferspitz 18
82152 Martinsried/Planegg
Germany
E-Mail: schulman@biochem.mpg.de
www.biochem.mpg.de/schulman
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Prof. Dr. Wolfgang Baumeister
Emeritus Group Molecular Structural Biology
Max Planck Institute of Biochemistry
Am Klopferspitz 18
82152 Martinsried/Planegg
Germany
E-Mail: baumeist@biochem.mpg.de
www.biochem.mpg.de/baumeister
Xiaomeng Tang, Lu Qu, Florian Wilfling, Florian Beck, Oliver P. Ernst, Brenda A. Schulman, Wolfgang Baumeister, Cordula Enenkel: Metabolically regulated proteasome supramolecular organization in situ, Cell, January 2026
DOI: 10.1016/j.cell.2025.12.035
https://www.cell.com/cell/fulltext/S0092-8674(25)01485-0
- Summary of the study
https://www.biochem.mpg.de/structure-and-function-of-proteasome-storage-granules - Press Release on the website of the MPI of Biochemistry
Cryoelectron tomography reveals how proteasomes organize inside cells into paracrystalline structure ...
Source: Image: Xiaomeng Tang, Lu Qu
Copyright: MPI of Biochemistry
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