Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Guardians of the Gate


To travel between the cytoplasm and the nucleus, proteins must pass through a gateway called the nuclear pore complex (NPC). However, it is unknown whether the cell can monitor the proteins that go through the NPC. Using in situ cryo-electron tomography to look into cells that are frozen in a life-like state, scientists at the Max Planck Institute of Biochemistry discovered that NPCs are decorated with highly organized clusters of proteasomes, molecular machines that destroy misfolded and mislocalized proteins to ensure healthy cell function. These NPC-tethered proteasomes may perform surveillance of NPC trafficking to ensure that only the correct proteins pass into, or out of, the nucleus.

A gateway has opened between two universes. Invaders from one universe are coming through the gate, and if they make it through, the other universe will be thrown into chaos. Just when all hope seems lost, guardians arrive at the gate and fight back the invaders. This may sound like a scene from a science fiction movie or a comic book, but it is actually taking place at the gateway between the cytoplasm and nucleus inside a single cell.

Segmentation of a cryo-electron tomogram, showing the native cellular environment around the nucleus.

Benjamin Engel © Max Planck Institute of Biochemistry

Cellular Superheroes

Did you know that there are superheroes inside the cell? These heroes are called proteasomes. They are large protein complexes that defend the cell by destroying misfolded and mislocalized proteins. Without protection from the proteasomes, cells eventually die because they are unable to get rid of these dangerous proteins. While the importance of proteasomes is clear, it is unknown whether proteasomes localize to cellular regions that need their help the most. How can the cell ensure that there are enough proteasomes at the right place, at the right time? To explore this question, researchers in the department of molecular structural biology used in situ cryo-electron tomography (cryo-ET) to visualize proteasomes within their native cellular environment.

Freeze! Snapshots of Proteins in Action

To perform in situ cryo-ET, cells are rapidly frozen and then thinned with a focused ion beam to make transparent “windows” into the cells that can be imaged by a transmission electron microscope. The resulting three-dimensional images, called tomograms, reveal the crowded environment of the cell in its native state and at a resolution that is high enough to see the fine details on protein structures. “It’s a revolutionary technique,” explains Sahradha Albert, first author of the study. “We are diving into a whole new world – a world that has been invisible to us until now. This study contains the most cellular tomograms ever combined for one project. Imaging so many proteasomes gave us the power to use structural averaging to see the functional states and binding interactions of each proteasome. We then placed each of these proteasomes back into its cellular context.”

A New Function for Proteasomes: NPC Surveillance

To their surprise, Albert and colleagues discovered that many proteasomes were attached to NPCs, which serve as gateways for the transport of molecules between the cytoplasm and nucleus. Using high-resolution averaging and nanometer-precision localization, they observed that tethering proteins attach these proteasomes to two sites on the nuclear side of the NPC: the NPC’s nuclear basket and the membrane encircling the NPC. The averages also revealed that these proteasomes are functional— they were caught in the act of destroying proteins.

It is well known that in order for larger proteins to pass through the NPC, they must be guided by a protein called importin. But is this guide enough to ensure that only the right proteins make it through the gate? Membrane proteins and small soluble proteins are able to diffuse through the NPC without importin. What if unwanted proteins slip through? The NPC-tethered proteasomes may provide an answer. By encircling the NPCs, these proteasomes could be part of a “border control” surveillance mechanism, where undesirable proteins coming through the NPC are identified and destroyed. “This striking new observation provides a whole new perspective on the regulation of NPC trafficking,” says Benjamin Engel, corresponding author of the paper. “It raises many questions. Our study is really just the tip of the iceberg.”

Putting the Superhero Team Together

Proteasomes do not defend the cell on their own. Like most superheroes, they require a support team. While proteasomes are powerful degradation machines, they need the help of other proteins to tell them where to go and what to destroy. The high-resolution structures generated by Albert and colleagues revealed that tethers are bound to the NPC-localized proteasomes. However, it remains a mystery what proteins build these tethers and how they recruit proteasomes to the NPC. Proteasomes degrade proteins that have been marked with poly-ubiquitin chains, modifications that are added by a class of enzymes called E3 ligases. The cell has hundreds of different versions of this enzyme, and each recognizes different substrates. This provides specificity for protein degradation, as the E3 ligases selectively tell the proteasomes what to destroy. The question is, which E3 ligases are acting at the NPC? “We know the proteasomes are performing an important task at the NPC, which we think is the surveillance of proteins passing through the gate,” say Engel. “However, the next step is to identify the proteins that work with the proteasome at the NPC. What are the members of the team, how do they function together, and what proteins are they degrading? Once we learn this, then we will understand how and why the proteasomes are guarding the gateway to the nucleus.”

Original publication:
Albert S, Schaffer M, Beck F, Mosalaganti S, Asano S, Thomas HF, Plitzko JM, Beck M, Baumeister W, Engel BD. Proteasomes tether to two distinct sites at the nuclear pore complex. PNAS, December 2017.

Dr. Benjamin Engel
Dept. of Molecular Structural Biology
Max Planck Institute of Biochemistry
Am Klopferspitz 18
82152 Martinsried

Dr. Christiane Menzfeld
Public Relations
Max Planck Institute of Biochemistry
Am Klopferspitz 18
82152 Martinsried
Phone: +49 89 8578-2824

Weitere Informationen: - homepage max planck institute of biochemistry

Dr. Christiane Menzfeld | Max-Planck-Institut für Biochemie

More articles from Life Sciences:

nachricht One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie

nachricht The dark side of cichlid fish: from cannibal to caregiver
20.04.2018 | Veterinärmedizinische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Spider silk key to new bone-fixing composite

University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

Im Focus: Basel researchers succeed in cultivating cartilage from stem cells

Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.

Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...

Im Focus: Like a wedge in a hinge

Researchers lay groundwork to tailor drugs for new targets in cancer therapy

In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

Latest News

Atoms may hum a tune from grand cosmic symphony

20.04.2018 | Physics and Astronomy

New research could literally squeeze more power out of solar cells

20.04.2018 | Physics and Astronomy

New record on squeezing light to one atom: Atomic Lego guides light below one nanometer

20.04.2018 | Physics and Astronomy

Science & Research
Overview of more VideoLinks >>>