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How to shoot the messenger
Date:1/26/2010

Hamburg, 26 January 2010 Cells rely on a range of signaling systems to communicate with each other and to control their own internal workings. Scientists from the European Molecular Biology Laboratory (EMBL) in Hamburg, Germany, have now found a way to hack into a vital communications system, raising the possibility of developing new drugs to tackle disorders like neurodegeneration, cancer and cardiovascular disease. In a study published today in Science Signaling, they have pieced together the first snapshot of what two of the system's components look like while interacting.

One way these signalling systems work is by triggering a flood of calcium ions inside the cell. These get picked up by a receiver, a protein called calmodulin which turns this calcium signal into action by switching various parts of the cell's machinery on or off. Calmodulin regulates a set of proteins called kinases, each of which controls the activity of specific parts of the cell, thus altering the cell's behaviour.

Using high-energy X-rays produced by the European Synchrotron Radiation Facility (ESRF) in Grenoble, France, and by the German Synchrotron Radiation Centre (DESY), in Hamburg, Germany, Matthias Wilmanns' team at EMBL revealed the molecular structure of one of these kinases, a protein called Death-Associated Protein Kinase DAPK, when bound to calmodulin. The structure showed how calmodulin binds to a particular section of DAPK, switching the kinase on so that it can go and change the function of its targets. The team then worked out which of DAPK's building blocks, or amino acids, were crucial for calmodulin to bind.

"Faulty versions of DAPK are involved in the development of some cancers," says Wilmanns, "so we want to know more about how this protein functions to allow its better exploitation as an anti-cancer target."

What's more, DAPK has physical similarities to many of the other kinases controlled by calmodulin, meaning many of them are l
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Contact: Sonia Furtado
sonia.furtado@embl.de
European Molecular Biology Laboratory
Source:Eurekalert  

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