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 More genes are active in high-performance maize
19.01.2018 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht How plants see light
19.01.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

All Focus news of the innovation-report >>>



Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

Latest News

Let the good tubes roll

19.01.2018 | Materials Sciences

How cancer metastasis happens: Researchers reveal a key mechanism

19.01.2018 | Health and Medicine

Meteoritic stardust unlocks timing of supernova dust formation

19.01.2018 | Physics and Astronomy

More VideoLinks >>>