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Regulation through protein degradation

Proteins that are involved in the development of an organism must be activated at the right time and then inactivated if no longer required. The specific degradation of these proteins through specialised and highly selective systems is an important protein inactivation mechanism that is being investigated by molecular scientist Prof. Dr. Claus Schwechheimer.

During the growth and development of plants, cells have to divide and differentiate into different tissue types. These processes need to be controlled by regulatory proteins that must be produced at the correct time and then inactivated if no longer required. The most efficient way to inactivate proteins is by specific and controlled degradation. “Signalling proteins must be removed after a certain time; otherwise the cells would be receiving a permanent message, and coordinated growth would be impossible,” said Prof. Claus Schwechheimer from the Centre of Plant Molecular Biology at the University of Tübingen. Claus Schwechheimer, who will shortly take up a post as chair at the Technical University in Munich, is involved in research into the complex protein machinery that regulates the degradation of other proteins. He carries out his research on the plant Arabidopsis thaliana, a popular laboratory plant commonly used by plant geneticists.

Investigation of cell constituents that control animal and human growth

Since many of the degradation-relevant protein complexes were initially discovered in plant cells, but are present in all higher organisms, including yeasts, worms and humans, the results of Schwechheimer’s research group can be transferred to the function of cells in other organisms. On the other hand, well-understood processes in non-plant organisms can have a positive effect on his work on plant proteins. One of the interests of Schwechheimer’s research group is the role of targeted protein degradation during cell division. Schwechheimer hopes that his research will provide him with insights into the fundamental processes in cells.

An Arabidopsis mutant serves as model organism

The innocuous Arabidopsis plant serves as model organism (Photo: Eric Melzer) © Eric Melzer
The researchers learned about the processes of targeted protein degradation through a strange Arabidopsis mutant that had an accidental genetic modification: dark-grown seedlings of this mutant in which the COP9 signalosome does not work, exhibit many morphological characteristics of light-grown seedlings. “It is interesting to note that the protein complex was initially discovered and characterised in plants. Basic cellular processes are usually discovered in humans, during disease research, for example,” said Schwechheimer. The researchers showed that the COP9 signalosome activates E3 ligases, which, in turn, are important for the specific degradation of proteins. COP9 mutants did not activate E3 lipases. “There are nearly a thousand E3 ligases in plant cells; they are required for the degradation of specific proteins,” said Schwechheimer. About five per cent of the plant genome codes for ligases. “This suggests a tight regulation of E3 ligases. However, at the moment we only know of a few E3 ligases and the proteins they degrade.”

The examination of E3 ligases is difficult

The failure of one E3 ligase can often be compensated by another, so that the loss does not impair the plant’s growth. On the other hand, only the protein that is degraded by the E3 ligase can provide information about its function; and it is difficult to identify these proteins. As regards the research of E3 ligases, it is important to note that the Arabidopsis genome was sequenced completely in 2000. The similarity of E3 ligase gene sequences provides information on whether they have a similar function and are potentially able to replace each other’s function. In terms of E3 ligase research, it is also important to know that there are many Arabidopsis mutants. Mutants with a defective E3 ligase can easily be identified and combined with other mutants. Before the entire Arabidopsis genome was available, it was only possible to clone individual proteins and reconstruct them from the genes by way of a cumbersome process, said Claus Schwechheimer: “This took a long time. The knowledge of the genome and the availability of the collection of mutants enables us to work much faster. This method is known as reverse genetics, and can be used for yeast and Arabidopsis but not for mice and men.”

Plant hormone works like an adhesive

In plants, light and growth hormones are the typical signals for the activation of E3 ligases. “In many plant signalling pathways, there are only a few steps between the detection of the signal and the degradation of the protein,” said Claus Schwechheimer. Auxin, an important plant hormone works like an adhesive: the E3 ligase binds on one side and the protein that has to be degraded binds on the other side of the protein. In contrast to protein-degrading complexes found in similar form in higher plant and animal cells, plant hormones have no equivalents in animals, and are specific for plants.

However, the E3-ligase dependent processes involved in the division of cells are highly conserved in all organisms. During cell division, each of the two new cells receives a strand of the original double-strand DNA. An important control mechanism is that the cell checks after duplication of the DNA whether the original DNA was correctly copied. If this is not the case, then repair mechanisms are activated. “Our investigations with Arabidopsis COP9 signalosome mutants have shown that these mutants have defective DNA strands. It is assumed that this is the reason for the impaired growth of the mutants. One must also assume that the failure of the same protein complex also stops growth in humans due to DNA damage,” said Claus Schwechheimer. The false repair of such DNA damage, especially when they occur in large numbers or if both DNA strands break, can lead to cell death or to the uncontrolled division of cells. Claus Schwechheimer hopes that the work he is doing in cooperation with his colleagues from medical research will help him discover the cause of this DNA damage, which is most likely an incorrectly degraded protein.

Source: Press release University of Tübingen - 28 August 2008
Further information:
Prof. Dr. Claus Schwechheimer
Centre of Plant Molecular Biology (ZMBP)
Developmental Genetics
Auf der Morgenstelle 5
72076 Tübingen
Tel.: +49 (0) 70 71/2 97 66 69
Fax: +49 (0) 70 71/29 51 35
E-mail: claus.schwechheimer@zmbp.uni-tuebingen.de
Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/regulation-through-protein-degradation