McsB – a new kid on the block

Researchers at the IMP have identified a bacterial enzyme that transmits signals in a previously unknown way. The discovery, reported in the current issue of the journal Science, could enable the development of novel, targeted antibiotics.

Proteins are chains of amino acids that fold to form three-dimensional structures. They are produced by the cell's own machinery, which translates the instructions of genes into the sequence of the chain links. One gene – one protein. For a long time this was a dogma of molecular biology. In the meantime, numerous modifications with which proteins can be spiced up after their synthesis by attaching small molecules, forming chemical bridges, splitting off amino acids or attaching and cutting protein chains. The functional spectrum of proteins is dramatically expanded.

The variety of regulatory possibilities also explains the paradox of the relatively small
number of genes in humans. One of the most frequent and important modifications is phosphorylation. Through addition and cleavage of phosphate residues, the function of a protein can be controlled very precisely. As with a molecular switch, enzymes, for example, are switched on and off in this way. The cell uses the reversible system to take up and transmit signals, among other things. The mechanism is tried and tested and has been retained from single-celled bacteria to humans.

The carriers of the phosphate residues, the kinases, therefore play a central role in the metabolism of all organisms. They are also involved in the development diseases and the growth of tumours and are therefore an important target for the development of new, selectively acting drugs.

Scientists at the Research Institute of Molecular Pathology have now identified a new class of kinases. Using biochemical and structural biological methods, the group led by Tim Clausen has succeeded in identifying a so-called protein arginine kinase. The researchers isolated the enzyme from Bacillus stearothermophilus, a thermophilic soil bacterium. In the upcoming issue of the journal SCIENCE, they describe their findings and methods.

The newly described kinase is called McsB and plays a role in the bacterium's stress response. Dealing with stress - such as heat, for example - is a major challenge for all living organisms. Microorganisms in particular have often developed astonishing strategies. Bacteria that invade cells and trigger diseases are all the more virulent the better they are able to against fever.

B. stearothermophilus itself is not a pathogen, but it can spoil food. The organism feels most comfortable at temperatures of around 55 degrees. For the researchers, this has the advantage that its proteins are very stable and can withstand even the harshest examination methods.

The enzyme McsB becomes active during heat stress. It transfers a phosphate residue to a
regulatory protein called CtsR, which is normally bound to DNA and blocks the transcription of stress genes. Phosphorylation changes the charge ratios and the binding to the DNA is lost.

What makes the process so interesting for science is that McsB attaches the phosphate group to the amino acid phosphate group to the amino acid arginine and not to serine as is usually the case, threonine or tyrosine. The proof of this was not easy to provide, for the analysis of phosphoarginine a new method first had to be developed.

The close collaboration with the service group for mass spectrometry under Karl Mechtler was particularly helpful. The research group Emmanuelle Charpentier at the neighbouring Max F. Perutz Laboratories under was also involved in the project – making it an example of successful interdisciplinary collaboration at the Campus Vienna Biocenter.

For IMP doctoral student Jakob Fuhrmann, first author of the publication, the work opens up exciting prospects for the future. ‘The new and rare signalling pathway could become medically interesting, for example as a target for specifically acting antibiotics,’ explains Fuhrmann.

After all, pathogens such as staphylococci and listeria are close relatives of the investigated bacillus and possess the same stress genes. In a next step, the IMP researchers now want to investigate whether protein arginine kinases also occur in humans. If they are exclusive to microorganisms, intervention with drugs would be particularly targeted and have few side effects.

About Tim Clausen

Born in Flensburg, Tim Clausen studied biology at the University of Constance. In 1997 he completed his doctorate at the Technical University of Munich and returned to Constance for his habilitation. From 1999, Tim Clausen headed a research group at the Max Planck Institute of Biochemistry in Martinsried for three years. In 2002, he moved to Vienna to join the Research Institute of Molecular Pathology (IMP), where he set up a new group for protein crystallography. From 1 July 2009, he will take up the position of IMP Senior Scientist.

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