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Nils Johnsson delivers initial insights

Nils Johnsson’s work focuses on communication research involving living objects. The 48-year-old biochemist is investigating how proteins manage the complicated process of cytokinesis, the division of the cell plasma. Thanks to a specific method, Johnsson is able to detect when proteins are interacting with each other.

The scientist has finally returned to Baden-Württemberg where his academic career initially began. Johnsson did his studies in Tübingen and subsequently accepted a post at the Max Planck Institute (MPI) for Biophysical Chemistry in Göttingen, where he did his degree and doctoral theses under the supervision of Professor Klaus Weber. Johnsson described how he cut up intestines in the local abattoir, scraped off cells and purified proteins for his doctoral thesis. Johnsson’s real wish was to investigate proteins in their natural environment, which eventually led him to accept a post at the MIT under yeast cell researcher Alexander Varshavsky and he later moved to the California Institute of Technology.

One of the first “tenants” in the new research centre

Prof. Dr. Nils Johnsson (photo: Pytlik)
Johnsson returned to Germany in 1995 and continued his work at the MPI for Breeding Research. He focused on the characterisation of proteins in the living cell (yeast) and filed a patent for a method that he developed. Six years later, Johnsson moved to Karlsruhe, where he accepted a post at the Institute of Genetics and Toxicology at the Karlsruhe Research Centre. In 2005, he became professor at the Centre for Molecular Biology and Inflammation at the University of Münster. And recently, Johnsson and his family moved to Ulm where he heads up the Institute of Molecular Genetics and Cell Biology at the new life sciences centre. He has already started working with his “neighbour”, Lenhard Rudolph.

“Chemistry in the smallest space”

As a basic researcher, Johnsson knows very well what Sisyphus work means. However, he is still fascinated by his favourite research objects – proteins. He is fascinated by how these molecular machines are able to function in a small space, by their precision and by the difficult conditions they have to tolerate. “In terms of cell biology, this is chemistry in a very small space, i.e. in a fluid environment. Electroengineers are surprised to see how mobile elements are used to set up robust and flexible circuits.

The centre of attention: proteins at the central switches

A daughter cell that has just separated from the mother cell. The cap (blue) of the cell is formed by a protein that was embedded in the wall that formed between daughter and mother cell during cell division. The red and green part of the cell show the sy
A daughter cell that has just separated from the mother cell. The cap (blue) of the cell is formed by a protein that was embedded in the wall that formed between daughter and mother cell during cell division. The red and green parts of the cell show the synthesis of the protein during earlier phases of cell growth. (Photo: Johnsson)
Johnsson focuses mainly on cytokinesis, the division of the cell plasma. The process, which actually consists of several processes, is very complex. Johnsson is hoping to find out how these processes are connected with each other and which proteins govern important functions. At present, Johnsson’s group of researchers is working on a kind of map of the proteins involved in cytokinesis in order to then identify the proteins that are located at important control points. The researchers are using genetic, biochemical and cell biological methods to investigate the interaction of these proteins.

How do proteins coordinate these complex processes?

During cell division, mother and daughter cells have to ensure that the plasma membrane does not break. Sensors are constantly monitoring the cell division process and it is assumed that they send stop signals to the cytokinesis apparatus if the process is in danger of getting out of control. “There are sensors and signalling cascades that have to communicate with other proteins involved in cytokinesis in order to coordinate this process.” Johnsson said that further research is necessary to understand in greater detail the protein-mediated coordination at these key centres of cytokinesis.

Nils Johnsson uses a method that helps to study the interaction between gene products. The method was developed in 1994 by Nils Johnsson and Alexander Varshavsky at Caltech. The technique is based on split-ubiquitin, which enables the measurement of many protein-protein interactions simultaneously, even directly at the site where they occur. This has many advantages for the researchers: “We can investigate proteins that are known to interact with each other and we can also look for new interaction partners.”
The split-ubiquitin process: The proteins X1 and X2 were coupled to the N- (Nub) and C-terminal part (Cub) of ubiquitin (Ub). When X1 and X2 bind to each other, the two halves form an intact ubiquitin molecule and the reporter is cleaved off. The released
The split-ubiquitin process: The proteins X1 and X2 were coupled to the N- (Nub) and C-terminal part (Cub) of ubiquitin (Ub). When X1 and X2 bind to each other, the two halves form an intact ubiquitin molecule and the reporter is cleaved off. The released reporter protein serves as a signal for successful protein interaction. (Photo: Johnsson)

Fixed picture of a dynamic network

This is based on the idea that all cellular processes are governed by proteins and the interactions between them. Johnsson’s method is a kind of starting point, it only delivers a fixed picture of a dynamic and very flexible network. This is because the method only provides qualitative, and not quantitative, data, and provides no information on the binding strength of the two proteins and no information on the time and duration of the interactions during the cell cycle.
The yeasts on the plate synthesise different combinations of Nub and Cub fusion proteins. When a yeast cell synthesises a pair of interacting proteins, the released reporter safeguards the survival of the cells on a special selection medium. 96 different
The yeasts on the plate synthesise different combinations of Nub and Cub fusion proteins. When a yeast cell synthesises a pair of interacting proteins, the released reporter safeguards the survival of the cells on a special selection medium. 96 different protein pairs can thus be simultaneously tested to see how they interact with each other. In the picture, three pairs are clearly interacting. The photo below shows the growth of the yeast on a medium that does not reveal protein interactions. (Photo: Johnsson)

Basis for further investigations

This information is the basis for further investigations, for example for protein biochemical examinations, which are used to determine the affinities of the partners. The goal of this investigation is to find out the role of the partners during cytokinesis. In another investigation, Johnsson is hoping to find the alleles of genes that prevent the two proteins from interacting with each other. This will help the scientists to find out whether the lack of interaction has any effect on the processes; the Ulm researchers are hoping to mechanistically find out how these interactions are generated.

“One perspective is not enough”

According to Johnsson, the complex protein mechanisms in space and time can only be understood in detail by combining biomolecular imaging methods with other methods. One should see the researchers’ work as a kind of puzzle: different methods lead to completely different results, which rather than excluding each other most probably complement each other.

Yeast cells are the perfect organism

Johnsson is investigating these basic cellular processes in yeast cells and is well aware that yeast is not an issue of major interest to the public at large. However, this does not bother him; he sees Saccharomyces cerevisiae as the “perfect organism for his tests”. The tests can be done rapidly and efficiently because yeast cells regenerate quickly; their processes are similar to human processes and can be effectively genetically modified. According to Johnsson, the yeast proteome is the best known of all organisms. “Yeast is always a step ahead of other organisms” meaning that the genome is relatively simple and uncertainties therefore limited.

Some candidates are already known

Johnsson’s research group is investigating some 400 proteins, which correspond to about one tenth of the yeast proteome. This approach is somewhere between a proteome-wide approach and an approach that looks only at a few proteins. Although the cytokinesis protein family is constantly growing - hence leading to a growing number of proteins that have to be investigated (“that is Sisyphus work”) - Johnsson and his colleagues have already detected a few candidates, for example the CDC 24 protein or cell stress sensors. “There are already too many interesting proteins and no single research group is able to focus on all of them,” regrets Johnsson.

It is difficult to handle such a huge amount of data

The researcher thus touches upon a problem he and his colleagues are faced with: huge amounts of data. The generation of data is important, but the careful analysis of the data seems even more difficult and is equally as important, said Johnsson referring to artificial interactions and white spots on the (protein) map, which are not recognised as such. “This is an iterative process.”

Johnson is hoping to shed light on cytokinesis and will carry on with his experiments in order to achieve greater understanding. Since cell division is a universal process, Johnsson and his colleagues are hoping that this will also provide them with insights into the processes of higher cells. For example, there is evidence that disorders in the cell division process might lead to certain cancers.

A small amount of success generates motivation

The gaining of new knowledge is reminiscent of how a squirrel gathers its food. Johnsson is motivated by minor successes that potentially confirm initial hypotheses. “This encourages us enormously,” said Johnsson, who is well aware of the tremendous complexity of the cellular processes, for example the lipids of the cell membrane that organise protein clusters.

At the moment, Johnsson is settling into his life in Ulm, preparing both lectures and practical work. After a ‘relatively turbulent time’, he is focusing on expanding his research group and is utterly determined to find new cooperation partners to work with him in the new life sciences building in Ulm. Johnsson is aware of the fact that yeast cell biologists like himself are developing methods for investigating proteins and hence own tools that are also of interest for other researchers. Johnsson also knows very well that cooperation is most effective if the cooperating parties are only a few doors away from each other.

wp - 08.04.2008
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