Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Zooming-in on protein teamwork

03.11.2017

The surface of every cell contains receptors that react to external signals similar to a “gate”. In this way, the cells of the innate immune system can differentiate between friend and foe partly through their “toll-like receptors” (TLRs). Two parts of this gate often work together here, as researchers at Goethe University Frankfurt and their British colleagues have now found out with the help of a new super-resolution optical microscopy technique.

The surface of every cell contains receptors that react to external signals similar to a “gate”. In this way, the cells of the innate immune system can differentiate between friend and foe partly through their “toll-like receptors” (TLRs). Two parts of this gate often work together here, as researchers at Goethe University Frankfurt and their British colleagues have now found out with the help of a new super-resolution optical microscopy technique.


Left: Conventional light microscopy is an useful tool in visualising biological structures and processes. However, its resolution is not sufficient to study events occurring at molecular scale. The image on the left shows the nuclei of brain tumour cells (yellow: nuclei containing DNA) with Toll-like receptors 4 localised at the cell surface (cyan spots). Although many TLR4 can be clearly seen, the spatial resolution does not allow determination of single receptor units. Middle: Super-resolution microscopy greatly improves the spatial resolution and allows detection of single TLR4 clusters (cyan) at the surface of the cells. However, even at this superior resolution, it is not possible to distinguish between monomers and dimers of the receptor. Right: Crystal structure of a TLR4 dimer. The novel analysis method developed by the consortium is able to provide information allowing differentiating between receptor monomers and dimers.

Image rights: Widera/Heilemann

When the German Nobel Prize winner Christiane Nüsslein-Volhard discovered receptors in the fruit fly (Drosophila melanogaster) in the 1990s that transduced signals from the cell surface into a cellular response, she was amazed. She nicknamed the receptors “toll” (amazing) and this term has meanwhile become firmly established in scientific literature.

Since then, similar receptors (toll-like receptors) have also been discovered in animals and humans. They recognize bacteria, viruses and fungi and thus ensure that our body reacts to infections in a suitable way. By contrast, de-regulated TLRs can lead to chronic inflammatory conditions and cancer.

Experiments conducted so far indicated that TLRs are activated by a chemical signal that causes two proteins to cluster together as dimers. This process, which is known as “dimerization”, appears to play a pivotal role in a cell’s fate: It can decide whether the cell survives, dies or moves within the body.

Because dimerization takes place on a molecular scale that cannot be captured using conventional microscopy techniques, researchers have to date been dependent on indirect measuring methods. These were, however, prone to error and yielded diverging results. This has now changed thanks to the new super-resolution optical microscopy technique.

In the forthcoming issue of “Science Signaling”, the working groups led by Professor Mike Heilemann of Goethe University Frankfurt and by Dr. Darius Widera and Dr. Graeme Cottrell of the University of Reading in England describe how they have studied the organization of the TLR4 receptor on the cell surface in molecular resolution.

In a first step, they used a super-resolution microscope with a resolution about 100 times better than a standard fluorescence microscope. Since this was still not sufficient to make single receptor molecules in a tiny protein dimer visible, the researchers developed a more sophisticated analysis of the optical signal. In this way they were able to zoom in closer on the super-resolution images and examine under which conditions TLR4 forms a monomer or a dimer. The researchers could also detect which chemical signals from different pathogens modulate the receptors’ patterns.

The researchers hope that their work will lead in future to a better understanding of how TLR dimerization affects the decision between the life or death of a cell. It might also be possible to determine how pharmaceutical ingredients targeted at TLRs influence the behavior of cancer cells.

“It is also conceivable that this approach will help us in future to understand better the fundamental biological processes that regulate the immune system in health and disease. At the same time, this microscopy method is also applicable to other membrane proteins and many similar questions,” explains Professor Mike Heilemann from the Institute of Physical and Theoretical Chemistry at Goethe University Frankfurt.

Publication:
Carmen L. Krüger, Marie-Theres Zeuner, Graeme S. Cottrell, Darius Widera, Mike Heilemann: Quantitative single-molecule imaging of TLR4 reveals ligand-specific receptor dimerization, Science Signaling, doi: 10.1126/scisignal.aan1308

A picture can be downloaded under: http://www.muk.uni-frankfurt.de/68944753

Caption: Left: Conventional light microscopy is an useful tool in visualising biological structures and processes. However, its resolution is not sufficient to study events occurring at molecular scale. The image on the left shows the nuclei of brain tumour cells (yellow: nuclei containing DNA) with Toll-like receptors 4 localised at the cell surface (cyan spots). Although many TLR4 can be clearly seen, the spatial resolution does not allow determination of single receptor units. Middle: Super-resolution microscopy greatly improves the spatial resolution and allows detection of single TLR4 clusters (cyan) at the surface of the cells. However, even at this superior resolution, it is not possible to distinguish between monomers and dimers of the receptor. Right: Crystal structure of a TLR4 dimer. The novel analysis method developed by the consortium is able to provide information allowing differentiating between receptor monomers and dimers.

Image rights: Widera/Heilemann

Further information: Professor Mike Heilemann, Institute of Physical and Theoretical Chemistry, Faculty of Biochemistry, Chemistry and Pharmacy, Riedberg Campus, Tel.: +49(0)69-798- 29736, Heilemann@chemie.uni-frankfurt.de.

Tobias Lang | idw - Informationsdienst Wissenschaft
Further information:
http://www.uni-frankfurt.de

More articles from Life Sciences:

nachricht Jellyfish-inspired electronic skin glows when it gets hurt
02.11.2017 | American Chemical Society

nachricht Oregon team says physics explains protein unpredictability
02.11.2017 | University of Oregon

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Wrinkles give heat a jolt in pillared graphene

Rice University researchers test 3-D carbon nanostructures' thermal transport abilities

Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...

Im Focus: Support Free with “TwoCure” – Innovation in Resin-Based 3D Printing

The Fraunhofer Institute for Laser Technology ILT and Rapid Shape GmbH are working together to further develop resin-based 3D printing. The new “TwoCure” process requires no support structures and is significantly more efficient and productive than conventional 3D printing techniques for plastic components. Experts from Fraunhofer ILT will be presenting the state-funded joint development that makes use of the interaction of light and cold in forming the components at formnext 2017 from November 14 to 17 in Frankfurt am Main.

Much like stereolithography, one of the best-known processes for printing 3D plastic components works using photolithographic light exposure that causes liquid...

Im Focus: Researchers develop chip-scale optical abacus

A team of researchers led by Prof. Wolfram Pernice from the Institute of Physics at Münster University has developed a miniature abacus on a microchip which calculates using light signals. With it they are paving the way to the development of new types of computer in which, as in the human brain, the computing and storage functions are combined in one element.

Researchers at the universities of Münster, Exeter and Oxford have developed a miniature “abacus” which can be used for calculating with light signals. With it...

Im Focus: Lightwave controlled nanoscale electron acceleration sets the pace

Extremely short electron bunches are key to many new applications including ultrafast electron microscopy and table-top free-electron lasers. A german team of physicists from Rostock University, the Max Born Institute in Berlin, the Ludwig-Maxmilians-Universität Munich, and the Max Planck Institute of Quantum Optics in Garching has now shown how electrons can be accelerated in an extreme and well-controlled way with laser light, while crossing a silver particle of just a few nanometers.

Of particular importance for potential applications is the ability to manipulate the acceleration process, known as a swing-by maneuver from space travel, with...

Im Focus: Newly Discovered microRNA Regulates Mobility of Tumor Cells

Cancer cells can reactivate a cellular process that is an essential part of embryonic development. This allows them to leave the primary tumor, penetrate the surrounding tissue and form metastases in peripheral organs. In the journal Nature Communications, researchers from the University of Basel’s Department of Biomedicine provide an insight into the molecular networks that regulate this process.

During an embryo’s development, epithelial cells can break away from the cell cluster, modify their cell type-specific properties, and migrate into other...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

3rd Symposium on Driving Simulation

23.10.2017 | Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

 
Latest News

Classroom in Stuttgart with Li-Fi of Fraunhofer HHI opened

03.11.2017 | Science Education

Zooming-in on protein teamwork

03.11.2017 | Life Sciences

Atmospheric beacons guide NASA scientists in search for life

03.11.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>